review article the emerging roles of the calcineurin...

Review ArticleThe Emerging Roles of the Calcineurin-NuclearFactor of Activated T-Lymphocytes Pathway in NervousSystem Functions and Diseases

Maulilio John Kipanyula1 Wahabu Hamisi Kimaro1 and Paul F Seke Etet2

1Department of Veterinary Anatomy Faculty of Veterinary Medicine Sokoine University of Agriculture PO Box 3016Chuo Kikuu Morogoro Tanzania2Department of Basic Health Sciences Qassim University Buraydah Al-Qassim 51452 Saudi Arabia

Correspondence should be addressed to Maulilio John Kipanyula kipanyulasuanetactz

Received 13 May 2016 Accepted 21 July 2016

Academic Editor Elke Bromberg

Copyright copy 2016 Maulilio John Kipanyula et alThis is an open access article distributed under theCreative CommonsAttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegen-erative diseases Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes(NFAT) signaling pathway a Ca2+calmodulin-dependent major proinflammatory pathway in the pathogenesis of these diseasesNeurotoxins such as amyloid-120573 tau protein and 120572-synuclein trigger abnormal calcineurinNFAT signaling activities Additionallyincreased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator ofcalcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations in neurodegenerative diseases psychoticdisorders epilepsy and traumatic brain and spinal cord injuries Treatment with calcineurinNFAT inhibitors induces some degreeof neuroprotection and decreased reactive gliosis in the central and peripheral nervous system In this paper we summarizeand discuss the current understanding of the roles of calcineurinNFAT signaling in physiology and pathologies of the adultand developing nervous system with an emphasis on recent reports and cutting-edge findings CalcineurinNFAT signaling isknown for its critical roles in the developing and adult nervous system Its role in physiological and pathological processes is stillcontroversial However available data suggest that its beneficial and detrimental effects are context-dependent In view of recentreports calcineurinNFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditionsThis review further highlights the need to characterize better all factors determining the outcome of calcineurinNFAT signalingin diseases and the downstream targets mediating the beneficial and detrimental effects

1 Introduction

Cellular responses to calcium (Ca2+) mobilization are highlyversatile due to the ability of intracellular Ca2+ signaling toactivate an extensive repertoire of downstream signaling tar-gets [1 2] Among such molecules the calmodulin- (CaM-)dependent phosphatase calcineurin and its transcriptionfactors termed nuclear factors of activated T cells (NFATs) arereported as pivotal in a wide range of physiological processesincluding homeostasis angiogenesis myogenesis adipogen-esis osteogenesis chondrocyte differentiation cardiovascu-lar system development pancreatic 120573-cell proliferation hairfollicle cell differentiation and remodeling and activities of

cells of the immune and nervous systems [3ndash12] Overex-pressed and decreased activities of calcineurinNFAT path-way were also reported in pathologies affecting these func-tions [3 6 13ndash18]

A growing body of evidence suggests that calcineurinNFAT pathway plays critical roles in normal and pathologicalnervous system Over the last decade this signaling pathwaywas reported as major player in corticogenesis synaptogen-esis and neuritogenesis during mammalian nervous systemdevelopment [19ndash23] as well as myelination synaptic plas-ticity neurotransmission and central and peripheral nervoussystem cell proliferation migration and differentiation in themature nervous system [24ndash26] Altered calcineurinNFAT

Hindawi Publishing CorporationJournal of Aging ResearchVolume 2016 Article ID 5081021 20 pageshttpdxdoiorg10115520165081021

2 Journal of Aging Research

activation is increasingly linked to pathological featuresof neurodegenerative diseases such as amyotrophic lateralsclerosis Huntingtonrsquos Parkinsonrsquos andAlzheimerrsquos diseasescharacterized by massive synaptic dysfunction glial activa-tion and neuronal death in some regions of the brain [26ndash29] CalcineurinNFAT involvement has also been reportedin psychiatric disorders epilepsy and traumatic brain andspinal cord injuries [30ndash35] Moreover recent data also sug-gest that NFAT isoforms are selectively activated in neuronsand glial cells in nervous system diseases [36 37] and animalmodels [38ndash41]

Herein we discuss the current understanding of the roleof calcineurinNFAT signaling pathway in both physiologyand pathologies of the adult and developing nervous systemwith an emphasis on recent reports and cutting-edge findings

2 CalcineurinNFAT Pathway

21 Calcineurin Calcineurin also termed as proteinphosphatase B (PP2B) is a Ca2+CaM-dependent serinethreonine phosphatase It was described for the first time inthe bovine brain about 40 years ago [42 43] Calcineurin ismade up of a 61 kD CaM-binding catalytic subunit termedcalcineurin A (CnA) and a 19 kD Ca2+-binding regulatorysubunit named calcineurin B (CnB) stably associated(noncovalently) [44 45] To date three isozymes of thecatalytic subunit (CnA120572 CnA120573 and CnA120574) have beenreported There are two isoforms of the regulatory subunitnamely CnB1 and CnB2 In vertebrates each subunit isencoded by a separate gene PPP3CA PPP3CB and PPP3CCfor CnB1 and PPP3R1 PPP3R2 for CnB2 [46 47] The twocalcineurin isoforms are widely distributed in mammaliantissues Immunohistochemical studies showed that undernormal conditions calcineurin isoforms are highly expressedin neuroinflammation-sensible neurons like corticohypo-thalamic pyramidal cells and cerebellar Purkinje cellsas well as in peripheral nervous system (PNS) glia likeSchwann cells but not in central nervous system (CNS) glia[37 48 49]

The subcellular distribution of calcineurin is an impor-tant control point in regulating its activity Various studiesaddressed the subcellular localization of calcineurin in var-ious mammalian cells [2 50 51] In neurons calcineurin wasfound in the cytoplasm endoplasmic reticulum Golgi appa-ratus nucleus synaptic vesicles microsomes mitochondrionouter membrane and plasma membrane [2 48 49 51 52]

22 NFAT Transcription Factors NFAT proteins are a familyof transcription factors normally found in the cytoplasm ina hyperphosphorylated (inactive) state [53ndash55] This familycomprises five distinct gene products termed (i) NFATcNFAT2 or NFATc1 (ii) NFATp NFAT1 or NFATc2 (iii)NFATx NFAT4 or NFATc3 (iii) NFAT3 or NFATc4 and(iv) osmotic response element-binding protein (OREBP)tonicity-responsive binding-protein (TonEBP) or NFAT5[56 57] In the context of this review nomenclature ofNFATc1-c4 and NFAT5 will be used

NFATc1ndashc4 occur as monomers with unique aminoand carboxyl termini containing transcription activation

domains (TADs) and two conserved domains (i) a regulatorydomain termedNFAThomology region (NHR) which showsa lesser degree of pair-wise sequence identity but has severalstrongly conserved sequence motifs characteristic of theNFAT family and (ii) the Rel homology region (RHR) inthe C-terminus where the DNA binding domain (DBD) islocated [14 56] The NHR encompasses calcineurin dockingsites a nuclear localization signal (NLS) responsible forcalcineurin-mediated nuclear translocation and an extendedserine-rich region [44 58ndash61] On the other hand the DBDbinds DNA and interacts with partner proteins to transac-tivate gene transcription Examples of partner transcriptionfactors include AP-1 cell life and death regulators [dimerictranscription factors composed of activating transcriptionfactor (ATF) Fos or Jun subunits] and important oncogenicregulators likemyocyte enhancer factor-2 (MEF2) andGATAbinding protein 4 (GATA4) [60 62] Regions out of the reg-ulatory and DNA binding domains like TADs demonstraterelatively little sequence conservation [57 59] NFAT5 is ahomodimer with a distinct domain structure This isoformretains only the RHR region of homology to the Ca2+-regulated isoforms whilst the remaining 600 amino acids arecompletely different The DBD of NFATs is distantly relatedto the DBD of nuclear factor kappa B (NF-120581B)Rel familyallowing them to be classified sometimes as members of thisextended family [63 64]

NFATs regulate the transcriptional induction of genesencoding for immune modulatorsactivators such as gran-ulocyte-macrophage colony-stimulating factor (GM-CSF)forkhead box P3 (FOXP3) immunoglobulin kappa (Ig120581)gamma interferon (IFN120574) CD5 CD25 CD28 CD40interleukin- (IL-) 2 IL-3 IL-4 IL-5 IL-13 IL-8 Th2-typecytokine IL-31 Fas ligand macrophage inflammatory protein1 alpha (MIP-1120572) protein tyrosine kinase Syk cyclooxygenase2 (COX-2) and tumor necrosis factor alpha (TNF-120572) and itsfamilymember BlyS NFATsmay also control genes encodingsignaling molecules as variate as Ca2+ regulators [inositol145-trisphosphate (IP

3) receptor (IP

3R) regulator of cal-

cineurin 1 (RCAN1)] growth factors (VEGF neurotrophins)myelination genes (P0 and Krox-20) glucose regulationgenes (insulin HNF1 PDX and GLUT2) cell cycle anddeath regulatoractivators [p21Waf1 c-Myc cyclin-dependentkinase 4 (CDK4) B-cell lymphoma 2 (Bcl-2) and cyclinsA2 D1 and D2] oncogenes (Wnt 120573-catenin) microRNAs(miR-21 miR-23 miR-24 miR-27 miR-125 miR-195 miR-199 and miR-224) and surfactants (sftpa sftpb sftpc andabca3) [9 65ndash74] NFAT isoforms are ubiquitously expressedand are generally regulated by Ca2+ signaling with exceptionof NFAT5 [59 75 76] NFAT5 regulates hypertonic stress-induced gene transcription whereas the other NFATs actas integrators of Ca2+ driven signaling pathways in geneexpression and cell differentiation programs [57 77 78]

All Ca2+-regulated NFATs (NFATc1ndashc4) are expressed inneurons [79]The previously assumed functional redundancyof NFAT functions was proved wrong by their wide-rangingexpression profile among cell types under both physiologicaland pathological conditions For example loss of specificNFAT subtypes resulted in cardiovascular skeletal muscle

Journal of Aging Research 3

cartilage neuronal andor immune system defects [54 5980 81] In addition Vihma and colleagues reported thatNFAT subcellular localizations and transcriptional activitiesare isoform- and cell type-specific [37] In that contextthe strongest transcriptional activators were NFATc3 andNFATc4 in primary hippocampal neurons and NFATc1 andNFATc3 in human embryonic kidney-derived HEK293 cells

23 Signaling Activation Theactivation of calcineurinNFATsignaling pathway involves three key steps (i) NFAT proteindephosphorylation by calcineurin (ii) nuclear translocationof NFATs and (iii) increased affinity for DNA Ligand-receptor interaction activates phospholipase C (PLC) result-ing in the release of IP

3 which in turn leads to the release

of Ca2+ from intracellular stores through IP3Rs [59 82]

Notably Ca2+ release from the intracellular stores requiresa stimulus capable of generation of second messengersthat trigger Ca2+ release from intracellular stores in theendoplasmicsarcoplasmic reticulum via channels of IP

3R1ndash

3 and ryanodine receptors (RyR1ndash3) [59 83ndash87] Like forother Ca2+CaM-dependent enzymes calcineurin activationrequires increase in cytosolic Ca2+ levels Such activationmayresult from the binding of Ca2+ to calcineurin B subunitor from the binding of Ca2+-activated CaM to calcineurin[50] In turn calcineurin activates NFATs by dephospho-rylating multiple N-terminal phosphoserine residues in theregulatory domain Such dephosphorylation increases NFATaffinity forDNA [59]Thedephosphorylation results in a con-formational change in the NFAT molecule that exposes thenuclear localization signal allowing NFAT nuclear translo-cation to take place presumably through nuclear pores[88] In the nucleus NFATs become transcriptionally activeby forming complexes with other factors and coactivatorsproviding a direct link between intracellular Ca2+ signalingand gene expression Calcineurin also promotes nuclearretention of NFAT by masking nuclear export signals (NES)and preventing NES-dependent nuclear export [88 89]Moreover calcineurin mediated NFAT activation is mainlyrequired at resting state (resting membrane potential) wherethe amount of Ca2+ released from intracellular stores is notsufficient for direct NFAT activation [75 90]

24 Regulation and Pharmacology

241 Endogenous Regulation Regulators of calcineurin(RCANs) or modulatory calcineurin-interacting proteins(MCIPs MCIP1ndash3) belonging to the calcipressin family ofproteins play a pivotal role in regulating calcineurin activityThe RCANs are evolutionarily conserved proteins that candirectly bind and inhibit calcineurin The RCAN1 genesare found on chromosome 21 The RCAN gene encodesdifferent isoforms of protein namely RCAN1 RCAN2RCAN3 and RCAN4 where RCAN1 and RCAN4 are themain isoforms Furthermore it appears that RCAN1 has twoRCAN1 isoforms 1S with 197 amino acids and RCAN1Lwith 252 amino acids Previous studies have shown thatan aberration in RCANs activities decreases calcineurin-NFAT signaling activities Recent studies have shown that

RCANs can show both inhibitory and facilitatory roles inactivation of the calcineurin-NFAT signaling pathway Amechanistic explanation on how RCAN proteins preciselymodulate calcineurin function is still debatable OverallRCANs have been implicated to function primarily as chap-erones for calcineurin biosynthesis or recycling requiringbinding phosphorylation ubiquitylation and proteasomaldegradation for their stimulatory effect [50 91 92] Otherregulators including scaffolding proteins CAINCABIN-1and A-kinase anchoring protein 79 (AKAP79) have alsobeen identified to interact and inhibit calcineurin functionin a phosphorylation-dependent manner inmammalian cells(details given below)

242 Endogenous Inhibition The regulation of calcineurinNFAT activity is achieved (i) in the nucleus by activitiesof serinethreonine kinases promoting the export of nuclearNFAT (ii) in the cytoplasm through phosphorylation ofNFAT serine (SP) repeats and N-terminal domain which arecritical for NFAT activation and nuclear import [88 93 94]Various kinases were implicated in NFAT nuclear exportExamples include glycogen synthase kinase (GSK) proteinkinase A (PKA) casein kinase and also mitogen-activatedprotein kinases (MAPKs) like c-Jun NH

2- terminal kinases

(JNKs) and cellular stress-associated p38 kinase [14 54]Although different kinases have been implicated in regulatingNFATactivity the distinction between drivers and passengersin the cytoplasm and in the nucleus is still puzzling Notablyit is not clearly understood whether the kinases whichmediate rephosphorylation of nuclear or activated NFATs aresimilar to those that phosphorylate NFATs under basal stateconditions [14 54] Other early reports from targeted geneticand pharmacological manipulations suggest that members ofthe JNK family regulate both the import and export of NFATswhile p38 MAPKs mediate NFAT rephosphorylation thusNFAT nuclear export [13 89 95]

CalcineurinNFAT signaling blocking agents mainly actat calcineurin and NFAT levels They include cellular (pro-tein inhibitors) and pharmacological inhibitors Althoughnumerous endogenous proteins may have potential toinhibit calcineurin or NFAT activities only four are well-characterized (i) A-kinase anchoring protein 79 (AKAP79)a scaffold protein that prevents calcineurin-substrate inter-actions [96 97] (ii) calcineurin inhibitor (CAIN) orcalcineurin-binding (CABIN) proteins which block cal-cineurin activity [98 99] (iii) calcineurin homologousprotein (CHP) and (vi) modulatory calcineurin-interactingproteins (MCIP1ndash3) which prevent NFAT nuclear import bypreventing its phosphorylation [94 100ndash103]

243 Pharmacological Inhibition Two pharmacologicalinhibitors of NFAT translocation namely cyclosporine AFK506 (tacrolimus) and its ethyl analog ascomycin arecommonly used as immunosuppressants particularly inorgan transplantation [104ndash107] These chemically distinctmicrobial products inhibit calcineurin activity by bindingwith subnanomolar affinity to cytosolic proteins calledimmunophilins The resultant drug-protein composite bindstightly to calcineurin and blocks its phosphatase activity by


preventing substrate access [14 59] Cyclosporine A bindsto cyclophilin and FK506 binds to FK506-binding protein(FKBP) [88 108] These inhibitors indiscriminately blockall downstream calcineurin signaling including various sig-naling pathways collaboratingwith calcineurinNFAT signal-ing pathway [39 93] Such complete blockade of calcineurinactivities may explain at least partly the serious side effectsof cyclosporine A and FK506 [104 105] particularly inpediatric patients [106 107]

Recent studies in rat brain slices and cultured astro-cytes revealed that cyclosporine A increases reactive oxygenspecies (ROS) formation and alters glucose and energymetabolism partly by Krebs cycle inhibition and anaerobicglycolysis activation [109] These detrimental effects prob-ably participate in cyclosporine A neurotoxicity Addition-ally inhibition of NFAT activity suppressor GSK-3 medi-ated by wild-type mice chronic treatment with lithium orcyclosporine A resulted in increases in nuclear translocationof NFATc3 and Fas-dependent apoptosis in brain neuronsaccompanied by pronounced motor deficits [110] In thesame study neither neuronal loss nor motor deficits wereobserved in Fas deficient TetDN-GSK-3 mice suggestingthat GSK-3 contributes to the neurological toxicity inducedby cyclosporine ATherefore GSK-3 inhibitors may improvecalcineurin inhibitor neurotoxicity Cyclosporine A may alsomediate neuronal affection by decreasing biometal availabil-ity [111ndash113]

Moreover experimental evidence has shown increasesin spinal NMDA receptor activity as a result of calcineurininhibitor induced pain syndrome (CIPS) [114ndash116] A whole-cell patch-clamp study in spinal cord slices revealed thatthe effect may be mediated by the potentiation of pre- andpostsynaptic NMDA receptor activity in the spinal cord[114] In the same study it was shown that FK506 treatmentincreased drastically the amplitude of excitatory postsynapticcurrents mediated by NMDA receptor in dorsal horn neu-rons Inhibitors of the serinethreonine protein kinase caseinkinase II (CK2) involved in the upregulation of synapticNMDAR activity in neurons abrogated pain hypersensitivitycaused by FK506 [117 118] Nonetheless cyclosporine Aalso mediated neuropathic pain independently of NMDAreceptor [108 118] suggesting that the processes mediatingCIPS are complex and warrant further studies

Interestingly inhibitors that do not block calcineurinenzymatic activity per se but rather interfere with enzymetargeting of one or more of its substrates have recently beendeveloped and used For instance the inhibitors of NFAT-calcineurin association (INCA) compounds may interfereselectively with calcineurinNFAT interaction without pre-venting dephosphorylation of other calcineurin substrates[119 120] Substrate-selective enzyme inhibition representsan important progress over cyclosporine A or FK506-mediated complete blockade of calcineurinNFAT signalingThis development is expected to lead to the developmentof safer classes of calcineurinNFAT inhibitors Certainlythe beneficial actions of cyclosporin A and FK506 arecounterbalanced by serious toxicities attributed partly to theirinterference with calcineurin signaling in other cells andtissues Although INCA have nonspecific cytotoxic effects

they are generally considered to be less toxic than treatmentwith cyclosporine A or FK506

3 Nervous System Development

CalcineurinNFAT signaling pathway is multifunctional Inthe PNS calcineurinNFAT signaling was reported to havecritical roles in the survival proliferation and differentiationof both neural and glial precursor cells [22] highlighting itspotential role in tissue regeneration Similar lines of evidencesuggest that calcineurinNFAT plays critical roles in the regu-lation of the CNS development including corticogenesis andsynaptogenesis

31 Corticogenesis Evidence supporting the involvement ofthe calcineurinNFAT4 signaling pathway in corticogenesisincludes a study in developing mouse cerebellar granule neu-rons that reported a pivotal role in controlling the temporalregulation of nuclear factor 1 occupancy This serves as a keylink between membrane potential and dendritic maturationby a voltage-sensitive developmental switch [121] In additionthe multifunctional HMG-box transcription factor Tox anovel regulator of mammalian corticogenesis is regulated bycalcineurinNFAT signaling [19] Genetic and biochemicalanalyses in the developing embryo revealed that fibroblastgrowth factor- (FGF-) mediated calcineurin signaling maytrigger neural induction by increasing Smad15 transcriptionvia silencing of bonemorphogenetic protein (BMP) signaling[122] Furthermore store-operated Ca2+ entry (SOCE) acti-vation regulates gene transcription in the developing nervoussystem and mediates neural progenitor cell proliferationthrough calcineurinNFAT signaling [123ndash125]

The role of the calcineurinNFAT signaling in cortico-genesis is probably mediated by NFATc3 the predominantNFAT isoform in neural progenitor cell cultures which isalso a potent inducer of neural progenitor cell differentiationinto neurons and astrocytes [22 126] Interestingly activity-dependentNFATc3 accumulation in the nucleuswas reportedin pericytes from cortical parenchymal microvessels [127]and differential expressions of NFATc3 and NFATc4 werereported in developing rat brain and traumatic brain injurymodels where NFATc4 was primarily expressed by neuronsand NFATc3 by astrocytes [125 128] These observationssuggest that different NFATs are recruited at the same timein resident cells of damaged and growing nervous tissue indi-cating that characterizing the effects of suchNFAT changes inspecific cell types may provide new therapeutic targets forneurodevelopmental disorders

32 Synaptogenesis The complex interactions betweeninhibitory gamma-aminobutyric acid (GABA) and excita-tory NMDA receptor activities are required during synapto-genesis Furthermore this interaction plays an importantrole in the induction of immediate early genes necessaryfor effective changes in synaptic plasticity and long-termmemory formation through calcineurin-dependent trans-cription of the key brain-derived neurotrophic factor(BDNF) [20 23 129 130] Of particular interest forneurodevelopmental treatments is a recently reported novel


synthetic neurotrophic (BDNF and neurotrophin-like)compound that is able to induce neurite growth and conferneuroprotection [21] In addition the neurotrophin nervegrowth factor (NGF) is known to upregulate the key regulatorof plasminogen activation system and synaptogenic proteinplasminogen activator inhibitor 1 (PAI-1) in primary mousehippocampal neurons via calcineurinNFAT signaling [131]Protein kinase C (PKC)calcineurin signaling-mediateddephosphorylation of axon growth regulatory moleculegrowth-associated protein 43 (GAP43) at developingGABAergic synapses resulted in pathological processingmimicking neonatal hypoxia including misfolding ofgephyrin a protein critical for the organization of GABAreceptors [132] Calcineurin signaling also mediates theGABAergic synaptic modulation induced by transientreceptor potential vanilloid type 1 (TrpV1) a ligand-gatedchannel abundantly expressed in developing primary sensoryneurons [133 134] Certainly these observations suggestthat calcineurin signaling is involved in the development ofGABAergic synaptic functions in the CNS

Moreover GABA promoted the shrinkage and elimina-tion of synapses by suppressing local dendritic Ca2+ signalingin rat hippocampal CA1 pyramidal neurons via a mechanismdepending on calcineurin and on actin-binding proteincofilin [135] Similarlymore recent studies also suggested thatcalcineurin is a major signaling molecule in the selection ofsynapses a critical mechanism in the reorganization of thedeveloping and adult CNS mediated by the major inhibitoryneurotransmitter GABA [132 135 136]

33 Endosome Trafficking It is now widely accepted thatcalcineurin signaling is a major player in the control of thetrafficking and signaling of endosomes performing the ret-rograde signaling an event critical for the development butalso for the nervous system function [2 137 138] Calabreseand colleagues reported calcineurin signaling modulation asa key event in the differential regulation of dynamins majorplayers of synaptic vesicle recycling in nerve terminals ofdeveloping neurons [137] Notably these authors observedthat tetrodotoxin- (TTX-) mediated chronic suppression ofneuronal activity results in the suppression of dynamin 1clustering at nerve terminals and in an increase of clusteringof dynamin 3 partly mediated by calcineurin signalingsilencing In addition NGF-mediated calcineurinNFAT sig-naling is critical for the control of endosome trafficking inneurons [77 131 138] Such NGFcalcineurinNFAT controlof the trafficking of endosomes is under the control of theeffector protein coronin-1 and regulatory events such asthe phosphorylation of cAMP responsive element bindingprotein (CREB) which are also mediated by NGF receptortropomyosin receptor kinase type 1 (TrkA) [138]

Notably as other tyrosine kinase receptors the receptorsof neurotrophins may also activate NFATs via inhibition ofthe promoter of NFAT nuclear export GSK-3120573 independentof Ca2+ and calcineurin signaling For instance a studyassessing the physiological roles of estrogen-related receptorgamma (ERR120574) an orphan nuclear receptor highly expressed

in the nervous system during embryogenesis and over lifes-pan revealed its involvement in the regulation of dopamin-ergic neuronal phenotype Such effect was mediated by GSK-3120573-NFAT interactions independently of Ca2+calcineurinsignaling [139] Similar NGF facilitated NFAT-mediatedgene expression induced by mild depolarization in dorsalroot ganglion sensory neurons without changes in PLCactivity-dependent events including Ca2+calcineurin sig-naling Instead NGF effects were induced by phosphoinosi-tide 3-kinase (PI3K)Akt signaling triggered byTrkA receptoractivation which abrogated GSK-3120573 activity [77]

Furthermore calcineurin is universally involved in vesi-cle endocytosis [12] and alterations in its endocytic activ-ity may participate in the pathogenic processes of variouspsychiatric diseases For instance alterations in presynapticfunctions of the 120574 isoformof the calcineurin catalytic subunitsuch as synaptic vesicle cycling have been suggested tocontribute to schizophrenia where variations in calcineurinA120574 genePPP3CC are common in neurons [140] Deregulationof intracellular Ca2+ also associates with the disruption of fastaxonal transport (FAT) in the pathogenesis of Alzheimerrsquosdisease (AD) [141ndash144]

4 Nervous System Function

CalcineurinNFAT has critical roles in neuronal and glialcell activity and survival as well as resulting events funda-mental for nervous system function like neurotransmissionand synaptic plasticity and myelination as summarized inFigure 1

41 Synaptic Plasticity and Neurotransmission

411 Synaptic Connectivity and Plasticity CalcineurinNFATsignaling and other pathways activated by T-type Ca2+channel activation play critical roles in the shaping of synapticconnectivity of thalamocortical and nucleus reticularis tha-lami GABAergic neurons mediated by slow wave sleep [145]a process pivotal for the consolidation of recently acquiredmemories and for the restoration of synaptic homeostasisThis mechanism may be evolutionary conserved [54 146147] PLCcalcineurin signaling has been reported to regulatethe trafficking of GABA A receptor in layer 3 pyramidal cellsof murine barrel cortex [136] Furthermore the inhibition ofgroup I metabotropic glutamate receptors (mGluRs) IP3Rsor calcineurin in CA1 neurons resulted in the blockade of theheterosynaptic shrinkage [85 87] that drives circuit remodel-ing during activity-dependent refinement of the developingnervous system and during experience-dependent plasticityin the hippocampus This inhibition has been reported tonegatively affect long-term potentiation (LTP) [87]

Experimental evidence also suggests that calcineurinis a regulator of synaptic plasticity For instance axoninitial segment rapid shortening was partly mediated bycalcineurin-dependent mechanisms including phosphoryla-tion of voltage-gated Na+ channels in dentate granule cells[148] Rapid modulation of the axon initial segment the siteof action potential initiation is the major plasticity mecha-nisms used by neurons to control their excitability time from


IP3R1-3

ERstores

RyR1-3

Neuron Endoplasmicreticulum

membrane

(eg NMDA AMPA)Glutamate receptors

Cell membrane

(eg neurotrophinreceptors IGF1R TrkA

(NGF) and TrkB (BDNF))

Tyrosine kinasereceptor family

Calcineurin

NFATc

PLCIP3

Transcription factor complexes

(eg GSK3 RCAN1)Endogenous inhibitors (eg FK506 cyclosporine A)

Pharmacological inhibitors

(eg NFATc-NF120581B NFATc-SOX10)X

(iii) Apoptosis in neurodegenerative conditions

Cell type-dependent transcription

Astrocyte (i) Survival activation(ii) Beneficial inflammatory responses(iii) TNF-120572-mediated detrimental signals

microglia

Schwann cells (i) Survival proliferation (ii) Myelinating gene expressionoligodendrocytes

NuclearOther signalsreceptors

Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+Ca2+

opening Ca2+ channels

(ii) Functions neurotransmission synaptic plasticity (i) Maturation survival proliferation

(eg L-type Ca2+ channels)

Figure 1 CalcineurinNFAT signaling pathway Calcineurinnuclear factor of activated T-lymphocytes (NFAT) signaling activation in thenervous system is mainly induced by neurotrophins via their tyrosine kinase receptors glutamate receptors and nonligand-dependentreceptors such as voltage-gated Ca2+ channels in hippocampal neurons The genes transcribed and the effects of these signaling pathwaysare cell-type dependent Abbreviations AMPA 120572-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid BDNF brain-derived neurotrophicfactor GSK3 glycogen synthase kinase 3 IGF1R insulin-like growth factor 1 receptor IP

3R inositol 145-trisphosphate receptor NF-120581B

nuclear factor kappa B NFATc Ca2+-regulated NFATs NGF neurotrophin nerve growth factor NMDA N-methyl-D-aspartic acid RCAN1regulator of calcineurin 1 RyR ryanodine receptor TrkA tropomyosin receptor kinase type 1 TrkB tropomyosin receptor kinase type 2

seconds to days In another study decreases in resting Ca2+levels associated with prolonged blockade of synaptic activityresulted in the synthesis of retinoic acid which triggeredthe related homeostatic synaptic plasticity via a calcineurin-dependent mechanism in neurons [149] Moreover spino-genesis enhancement in hippocampal neurons by the steroidhormones dihydrotestosterone and testosterone was blockedby individual antagonism of PKC PKA calcineurin LIMkinase (LIMK) or the MAPKs Erk and p38 [150] Similarestradiol-mediated rapidmodulation of synaptic plasticity anessential process for synaptic regulation was abrogated byindividual targeting of PI3K PKC PKA calcineurin CaMkinase II (CaMKII) LIMK Erk or p38 in hippocampalneurons [151]

412 Learning and Neurotransmission Evidence of cal-cineurinNFAT involvement in learning and memory pro-cesses was provided by experimental models of neurode-generative disorders A study in PS1-M146V knock-in FADmice showed that decreased calcineurin activity is a commonphenomenon in aging-related memory decline and mayaccount for memory defects in AD together with mutationsin the gene encoding for GSK-3120573 substrate presenilin 1(PS1) [152] which are critical for amyloid-120573 (A120573) gen-eration In a study using a spinocerebellar ataxia type 3(SCA3) transgenic mouse model typical impairments ofmotor learning and cerebellar motor coordination resultedfrom altered long-term depression (LTD) of glutamatergictransmission in parallel fiber-Purkinje neurons [153] Suchalteration resulted mainly from transcriptional downregula-tion of PLC 1205734 IP3R1 and calcineurin B suggesting that

PLCIP3-Rscalcineurin signaling is required for cerebellar

LTD induction thus motor learning and coordinationCalcineurinNFAT signaling is also involved in neuronal

excitability and neurotransmission Under physiological con-ditions AKAP79150-mediated calcineurinNFAT signalingmay prevent neuronal hyperexcitability in hippocampal neu-rons by increasing the transcriptional expression of keyregulators of neuronal excitability like M-type K+ channels[154] PKCcalcineurinNFAT signaling contributes to themaintenance of cyclic nucleotide-gated (HCN) channels inthe hyperpolarized status critical for their mediation ofneuronal excitability decrease in the distal dendrites ofhippocampal CA1 pyramidal neurons [155] and membrane-derived bioactive phospholipid lysophosphatidic acid type1 (LPA1) triggers RhoARho kinase (ROCK)calcineurinsignaling to induce the internalization of the GABAA1205742subunit at inhibitory synapses [156]

42 Calcineurin-PKA Interactions The interplay betweencalcineurin and PKA signaling plays a critical role in thenegative-feedback mechanism driving homeostatic synapticplasticity [157] that is accounting for the compensationof excessive inhibition or excitation of neuronal activityAlthough calcineurinNFAT signaling mainly regulates axonterminal remodeling while PKACREB signaling controlssynaptic vesicle accumulation [158] many lines of evidencesuggest mutual inhibitory interactions between the activitiesof these signaling pathways Examples include the activity ofthese signaling molecules when anchored to AKAP79150PKA kinase activity triggered by anchoring to AKAP79150


resulted in the enhancement of Ca2+-dependent inactiva-tion of L-type Ca2+ channels while the activation of thephosphatase activity of AKAP79150-anchored calcineurinreversed such PKA action reducing Ca2+-dependent inacti-vation [96 159] The basal activity of AKAP79150-anchoredPKAmaintained L-type Ca2+ channel-calcineurinNFAT sig-naling functional coupling by preserving the phosphoryla-tion of these channels contrary to anchored calcineurin [159160] Interestingly such AKAP79150 activity mediated themodulation of roundabout axonal guidance receptors Robo23 and ligands Slit23 in brain regions involved in rewardlearning and memory processes like islands of Calleja andthe hippocampus [97]

Furthermore PKA can induce NFAT nuclear export[14 54] PKA activation by forskolin-stimulated cAMPincreased the stability and half-life of RCAN1 proteinenhancing its inhibitory effects on calcineurin [161] In arecent study in pilocarpine-induced status epilepticus amurine model of temporal lobe epilepsy (TLE) the nucleartranslocation of CREB-regulated transcription coactivator 1(CRTC1) which is a key regulator of CREB activity wasregulated by calcineurin activity in hippocampal neurons[24]

Opposite effects of calcineurin and PKA were alsoreported as key events in (i) the dynamic fission-fusion eventsthat determine the shape and function of mitochondria [162163] thus cell survival (ii) neuronal output stabilizationinduced by tonic dopamine via type 1 dopaminergic receptors[164] and (iii) the phosphorylationdephosphorylation ofserine 897 in the NR1 subunit of the NMDA receptor (pNR1)whose increases in phosphorylation were reported in acutemorphine withdrawal [30]

43 Myelination Available data suggest that calcineurinNFAT pathway participates in signaling cascades pivotal forSchwann cell myelination Early studies reported that (i)murine Schwann cells express all Ca2+-dependent NFATisoforms (ii) the promoter and upstream enhancer elementsof the myelinating factor Krox-20 contain NFAT bindingsites and (iii) NFATs recruited by Ca2+-dependent signalingcanmake transcriptionally active complexes with Krox-20 [993 165] Reporter assays showed that Krox-20 is NFAT targetgene and that calcineurin is upregulated in Schwann cellsexpressing Krox-20 [8 166] Moreover we reported using ratSchwann cell cultures and an in vitro model of myelinationthat promyelinating actions of calcineurinNFAT signalingincluding increases in the expression of the myelinatinggenes Krox-20 Periaxin and P0 require cAMP elevation[9] Notably in the absence of cAMP elevation increasein cytosolic Ca2+ failed to induce Krox-20 expression Fur-thermore cyclosporine A and FK506 abrogated Krox-20expression Comparable observations were reported morerecently by other authors [165 167]

Experimental evidence also suggests that the activationof calcineurinNFAT required for Schwann cell myelinationoccurs partly through neuregulin 1 (NRG1) stimulation [8168ndash170] A study in mice lacking calcineurin B in cells of theneural crest lineage showed that calcineurinNFAT signaling

is required for NRG1-mediated Schwann cell myelination[170] In this model NFAT activation failed Krox-20 levelsin Schwann cell were decreased and radial sorting andmyelination were markedly delayed [8 170] NRG1 additionto neuron-Schwann cell cocultures promoted the activationof NFAT isoforms and cooperative transcriptional activitiesof NFATc4 and SOX10 required for Krox-20 upregulation[168 169] In addition NRG1calcineurinNFAT signalingupregulates myelinating genes in Schwann cells [8 168 171]

Unexpectedly FK506 stimulated Schwann cell prolifera-tion and promoted the survival of oligodendrocyte inmurinemodels of traumatic spinal cord injury [172ndash174] suggestingthat this signaling pathway is involved in the maintenancethus activity of myelinating cells in both peripheral andcentral nervous systems Moreover NFAT1 hyperactiva-tion decreased experimental autoimmune encephalomyelitisinduced by myelin oligodendrocyte glycoprotein (MOG) akey regulator of CNS myelination [175 176]

5 Controversial Roles in NervousSystem Diseases

51 Neurodegenerative Diseases

511 Pathogenic Roles Increased calcineurin activity wasreported in both aging and AD models [27 177 178] Forinstance calcineurinNFAT signaling may mediate the aber-rant activity of deregulated plasma membrane Ca2+ pumps(PMCAs) a suggested link between brain aging and the onsetof neurodegenerative diseases [27 179 180]The strongestADgenetic risk factor the apoE4 allele encodes for apolipopro-tein E4 that has poor inhibitory abilities on calcineurinactivity unlike the neuroprotective apolipoproteins E2 andE3 [181ndash183] Apolipoprotein E4 also drives CNS functionalalterations associated with normal aging such as disturbedsleep [28 29]

Overactivated calcineurinNFAT signaling may con-tribute to synaptic plasticity affection in pathological con-ditions Notably in a postmortem study in human hip-pocampi high nuclear levels of NFATs observed at the earlystage of AD increased with cognitive decline severity [177]Additionally short exposure to A120573 oligomers resulted incalcineurin activation with transient changes in postsynapticproteins and morphological in spines while longer exposureresulted inNFAT activation andmarked spine loss in primarycortical neurons of wild-type mice [184] A120573-treatment ofmurine hippocampal neurons also resulted inCa2+ signaling-dependent defects in BDNF transport first in dendrites andthen in axons [40] Studies in mouse and rat models of severechildhood epilepsy revealed that calcineurinNFAT signalingmediates seizure-induced dendrite growth suppression inpyramidal neurons and thus the resulting learning andmem-ory impairment associated with this intractable condition[185]

NFAT signaling alterations in neurodegenerative diseasesare selective A report by Abdul and colleagues strongly sug-gested that such selective alterationmay play a key role inA120573-induced neurodegeneration [186] These authors observed


increases in calcineurin A activity and more marked shiftsof NFATc2 and NFATc4 to nuclear compartments in humanhippocampus with increased dementia severity while evenin rapid-autopsy postmortem human brain tissue NFATc1was unchanged NFATc2 was more active in AD patientswith mild cognitive impairment contrary to NFATc4 whoseexpression was mostly associated with severe dementiaStill in the same study changes in calcineurinNFAT4 weredirectly correlated to soluble A120573 levels in postmortem hip-pocampus while oligomeric A120573 strongly stimulated NFATactivation in primary rat astrocyte cultures In anotherstudy NFATc4 levels were significantly increased in brainsof APPPS1 transgenic mice (AD model) and NFATc4overexpression increased A120573 production in human myeloidleukemia SAS-1 cells [36] suggesting a role for NFATc4 inamyloidogenesis Mechanisms proposed for NFAT-mediatedamyloidogenesis in human and murine astrocytes includeincreases in the expression of the gene encoding for TMP21a p24 cargo protein involved in A120573 and A120573 precursor protein(APP) trafficking [187ndash190]

512 Beneficial Effects The role of calcineurin in aberrant 120572-synuclein-mediated midbrain dopaminergic neuron toxicitya hallmark of Parkinsonrsquos disease (PD) is controversialIn a study addressing the underlying intracellular mech-anisms driving 120572-synuclein-mediated neurodegenerationtransgenic expression of PD 120572-synuclein A53T missensemutation promoted calcineurinNFAT signaling suggestingthat this signaling pathway may contribute to the neurotoxiceffects of aberrant 120572-synuclein [191] Surprisingly in a studyusing cells from various models (ranging from yeast toneurons) although aberrant 120572-synuclein also seemed toinduce cellular toxicity via overactivation of Ca2+-dependentsignaling pathways calcineurin inhibition with FK506 alsoresulted in toxicity [192] suggesting that calcineurin maymediate both beneficial and toxic effects under stimulation byaberrant120572-synuclein Characterizing the precise downstreamtargets mediating calcineurin beneficial or toxic effects mayprovide more insights of the novel therapeutic targets forsynucleinopathies

Calcineurin also mediates some beneficial and toxiceffects of AMPA and NMDA receptors which are postsy-naptic site-located glutamate-gated ion channels critical forsynaptic plasticity Calcineurin translocation to synapses andincreases in its activity mediated by NMDA receptor traf-ficking were reported as critical components of mechanismsdriving rapid compression-induced dendritic spine plasticityin cortical pyramidal neurons that is the rapid trimming ofdendritic spines occurring about 12 hours after mechanicalcompression [38] A study using soluble A120573 treated incultured rat hippocampal neurons and cultured hippocampalneurons from APPSwe AD-transgenic mice suggested thatcalcineurin signaling mediates AD-like synaptic dysfunc-tion induced by tau protein partly via AMPA receptordownregulation [193] In that study soluble A120573 oligomer-induced deficits in AMPA receptor trafficking were mediatedby tau phosphorylation and mislocalization to dendriticspines FK506 abrogated all these alterations Concomitant

tau hyperphosphorylation and calcineurin overactivationwere also reported in mouse models of Huntingtonrsquos disease[41] On the other hand IL-6Janus kinase (JAK) signalinginduced neuroprotective anti-NMDA activities in culturedcerebellar granule neurons via calcineurin-dependent inhi-bition of activities of NMDA receptor subunits NR2B andNR2C and concomitant inhibitions of NMDA-induced L-type voltage-gated Ca2+ channel activity and intracellularCa2+ store release [194]

Moreover in AD pathogenesis insulin-like growth factor1 (IGF-1) that acts as a regulator of tau phosphorylation issilenced in activated astrocytes by A120573calcineurin-inducedrelease of IGF-1-binding protein 3 (IGFBP-3) but intrigu-ingly A120573 directly induces increases in tau phosphorylationand resulting neuronal death via a mechanism involvingthe silencing of NFAT export kinase GSK-3120573 [195] sug-gesting opposite roles for calcineurin in AD pathogenesisIGF-1 also protected motor neurons in SOD1 transgenicmice a widely used model of amyotrophic lateral sclerosisvia a calcineurin-dependent mechanism [196] Although itis now widely accepted that therapeutic benefits of IGF-1 treatment in neurodegenerative conditions may emergepartly from calcineurin-dependent inhibition of glial inflam-matory reaction mediated by preventing TNF-120572-inducednuclear translocation of NF-120581B [197ndash199] it is also clearthat the expression of TNF-120572 resulting in detrimentalneuroinflammation and functional alterations in neuronsis mediated by astrocytic and microglial calcineurinNFATsignaling [200ndash202] Studies in transgenic mice and in vitromodels of neuroinflammatory diseases providedmechanisticinsights into the context of these opposite roles Thesestudies showed that TNF-120572 activate calcineurinNFATNF-120581B canonical inflammatory pathway in quiescent astrocyteswhile in activated astrocytes IGF-1 released locally recruitedcalcineurin signaling to inhibit NF-120581B-NFAT transcriptionalactivity through activation of the purinergic receptor P2Y6[203 204] suggesting that the activation status of the cell isan important determinant of calcineurinNFAT activity thatis downstream targets

513 Pharmacological Inhibition and Endogenous Regula-tion The pharmacological inhibition of calcineurinNFATsignaling improved animal condition in a number of stud-ies in neurodegenerative diseases and models Examplesinclude ADmousemodels where pharmacological inhibitionof this signaling pathway decreased A120573 plaques reducedglial activation alleviated both A120573 synaptotoxicity and neu-rotoxicity and improved synaptic function [25 205ndash207]suggesting a therapeutic potential for calcineurin inhibitorsin AD Reports by Kim and colleagues from studies per-formed in presenilin 1-mutant model of AD provided somemechanistic insights into the cognitive decline improvementresulting from reducing calcineurin activation in affectedbrains [25 208] These authors observed that the inhibitionof abnormally increased calcineurin activity characteristic ofthe disease resulted in the stabilization of the phosphoryla-tion of GluA1 a subunit of Ca2+-permeable AMPA receptorsand promoted synaptic trafficking of Ca2+-permeable AMPA


receptors as well as the resulting improvement in animal cog-nition [25] Such improvement resulted at least partly fromthe restoration of Ca2+-permeable AMPA receptor-mediatedhippocampal LTP [208] Decrease in calcineurin complexeswith transmembrane AMPA receptor regulatory proteins(TARPs) like 120574-8 which can stop the trafficking of bothAMPA and to a lesser extent NMDA receptors [209ndash211]may also participate in this process Furthermore biometalmediated neurite elongation and neuritogenesis in neuroncultures via calcineurin silencing [111] and calcineurinNFATsignaling induced a reduction in NGF expression and neuriteoutgrowth in rat neonatal ventricular cardiomyocytes andcultured sympathetic neurons [212 213]

Not surprisingly considering the aforementioned obser-vations in studies assessing the roles of calcineurin in neu-rodegenerative disorders (Section 512) endogenous regu-lators like plasma membrane calcium ATPase (PMCA) andRCAN1 mediate opposite effects in inflammatory processesRCAN1 overexpression was reported to be pivotal in theprevention of sepsis and LPS-induced lethality [214] and inthe protection against brain ischemiareperfusion injury inmurine models [215] However interactions of PMCA andvascular endothelial growth factor (VEGF) which dampenedcalcineurinNFAT signaling also induced the overexpres-sion of both the counter-inflammatory factor RCAN14 andthe proinflammatory factor COX-2 in activated murineendothelia [214 216 217] Additionally RCAN1 overexpres-sion increased the susceptibility to oxidative stress in primaryneurons [218] and exacerbated Ca2+ overloading-inducedneuronal apoptosis [219] suggesting that the overexpressionof calcineurin regulator RCAN1 may link Ca2+ overloadingand oxidative stress in neurodegenerative disorders (Fig-ure 1) Such detrimental effects of RCAN1 were mediated byRCAN14 and not by the other isoforms detected in humanbrain RCAN11 [91 219] probably via PI3KAktmTOR sig-naling [220 221] Such mechanistic insight was provided bya system study based on combinations of single-cell experi-mentation and in silico simulations where RCAN1 effect oninflammation mediated by calcineurinNFAT appeared tochange according to cellular levels from inhibitory activity atlow levels to facilitative activity at high levels [221] Notablyin that study RCAN1 facilitative activity was switched onby nuclear export of GSK-3120573 indicating that targeting thefactors involved in this inhibitory mechanism of GSK-3120573-mediated NFAT nuclear export may have a therapeuticpotential in neurodegenerative diseases

Considering that RCAN1 overexpression is a hallmarkof Down syndrome [219 222] it can be hypothesized thatthis event also contributes to the pathogenesis of AD-like neuropathology typically observed in Down syndromepatients after their middle age [223 224] In additionthe activity of pituitary adenylate cyclase-activating peptide(PACAP) a neurotrophic peptide involved in nervous sys-tem development learning and memory was significantlydisturbed by changes in RCAN1 expression [225] RCAN1overexpression impaired neurotrophic support of sympa-thetic neurons by inhibiting TrkA endocytosis resulting inNGF signaling silencing and associated neurodevelopmental

deficits [92] Furthermore overexpression of RCAN1 or dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A(DYRK1A) another Down syndrome-associated proteinnegatively regulated NFAT-dependent transcriptional activ-ity and decreased NGF-mediated upregulation of PAI-1 levels[131] a key synaptogenic mechanism Intriguingly deficiencyof RCAN11 but not RCAN14 affected radial migration ofrat cortical neurons and caused periventricular heterotopia[226] suggesting that this RCAN11 isoform may mediatepositive RCAN1 effects in developing cortex Future studiesusing selective activations and inhibitions of RCAN1 isoformsmay reveal the mechanisms accounting for isoform-specificeffects in the developing cortex

52 Neurodegenerative Conditions and Other NervousSystem Diseases

521 Neurodegenerative Conditions Alterations in the auto-phagy of mitochondria the process that normally triggersdamaged organelle elimination are common in neurode-generative diseases and conditions [227ndash230] In a studyusing axotomized precerebellar neurons a model of focalcerebellar lesion-induced remote degeneration rapamycin-mediated autophagy resulted in an aberrant mitochondrialfission partly caused by increased calcineurin activity [227]The activity of a calcineurin docking motif present inthe mitochondrial fission mechanoenzyme dynamin-relatedprotein 1 (Drp1) contributed to mitochondrial fragmentationand ischemic neuronal injury in neuronal and nonneuronalcells [163] Additionally calcineurin inhibitors mitigatedmitochondrial fragmentation in ferric ammonium citrate-exposed HT-22 hippocampal neurons a model of iron over-load and neurodegeneration [231]

Further evidence for calcineurin involvement in ischemicinjury includes reports suggesting that abnormal increasesin the activity of this phosphatase mediated by disturbancesin axonal Ca2+ homeostasis may play a key role in sec-ondary damage of neurons and capillary vessels observedduring acute phase of diffuse axonal injury [173 232]Calcineurin signaling also mediated the activation of thecytoskeletal actin severing protein cofilin and the resultingneuronal death in oxygen-glucose deprivationreperfusionand chemical induced oxidative stress to in vitro modelsof ischemia [34] Moreover cyclosporine A prevented theapoptosis of astrocytes exposed to simulated ischemia in vitrovia a calcineurin and Erk12-dependent mechanism [233]and through the inhibition of cytosolic phospholipase A2-(PLA2-) mediated release of arachidonic acid [234]

Selective calcineurin signaling in neurons and astrocytesis a key player in neurodegenerative conditions An earlystudy addressing neuronal apoptosis induced by the abusedpsychostimulantmethamphetamine revealed pivotal roles forcalcineurin activation and resulting Fas ligand upregulationmediated by nuclear translocations ofNFATc3 andNFATc4 inrats [235] The potent hepatotoxin microcystin-LR (MCLR)mediated an upregulation of calcineurin and NFATc3 levelsin rat hippocampal neurons that resulted inmarked increasesin apoptotic and necrotic cell death [32] MCLR effect


was prevented by FK506 treatment In addition NFATc4mediated light-induced retinal ganglion cell apoptosis byupregulating Fas ligand (FasL) expression on retinal neurons[236] and the overactivation of calcineurinNFATc3 signal-ing induced the typical neuronal toxicity and functional alter-ations observed in murine developing hippocampal neuronsfollowing the inhalation of anesthetic isoflurane includingcognitive impairment [237] A recent study in this modelof postoperative cognitive dysfunction revealed that abnor-mal calcineurinNFAT signaling associated with isofluraneexposure may mediate its detrimental effects by promotingthe degradation of the survival molecule signal transducerand activator of transcription 3 (STAT3) [238] MoreovercalcineurinNFATc3 signaling in activated astrocytes played akey role in the induction of alterations in synaptic remodelingand homeostasis observed in the hippocampus in controlledcortical impact injury in rats [39 128 239] As expectedcalcineurin inhibition restored synaptic function and plas-ticity in the latter murine model of traumatic brain injuryand in murine models of traumatic spinal cord injury [172ndash174] partly by abrogating astrocyte activation and reactivegliosis which are pivotal events in neuroinflammation-mediated neuronal loss Notably calcineurinNFAT signalingis critical for astrocyte activation [205 240] In another studyin ischemic striatum and cortex and in cultured astrocyteswhere FK506 also induced neuroprotective effects the cal-cineurin inhibitor prevented astrocyte apoptosis mediated byglutamate signaling [241]

Altogether these observations suggest a role for cal-cineurinNFAT signaling in astrocyte and neuronal lossesobserved in nervous system injury Unexpectedly sublethalischemia increased neuronal resistance to excitotoxicity viacalcineurin-dependent mechanisms including cyclin E1 pro-tein increased expression and declustering of the delayedrectifying K+ channel Kv21 at highly phosphorylated soma-todendritic clusters [242] In addition preconditioning ofneurons with biometal ions (Cu2+ Zn2+) protected thesecells against NMDA receptor-induced excitotoxicity throughmetal chaperone PBT2-induced calpain cleavage of cal-cineurin [111 112] Thus calcineurinNFAT pathway partici-pates in the interplay between proinflammatory and counter-inflammatory signals in the nervous system further suggest-ing that unraveling the downstream targets accounting forbeneficial and neurotoxic effects of this signaling pathwaymay have a therapeutic potential in neurodegenerative con-ditions

522 Psychotic Disorders Early genetic studies showed thatpolymorphisms of the genes coding for either the catalyticor regulatory subunit of calcineurin isoenzymes are stronglyassociated with the risk for developing schizophrenia andother psychotic disorderswhose pathological features includedisturbances in Ca2+ signaling [46 243ndash246] A more recentgenome-wide weighted coexpression network analysis onneural progenitors and neurons from individuals with Tim-othy syndrome an autism spectrum disorder resulting frommutations in the gene encoding L-type CaV12 Ca2+ channelssuggested that the disease may be caused by disturbances

in transcriptional activities of Ca2+-dependent signalingmolecules like FOXproteinsMEF2 CREB andNFATs [247]

Furthermore GABA A receptor activation promoted adecrease in anxiety indicators and hippocampal neurogenesisvia the calcineurinNFAT4 signaling in mice suggestingthat pharmacological targeting of this signaling pathwaymay improve emotional disorders [248] Similar evidencefrom pharmacological and postmortem studies suggests thattreatment with antipsychotics aimed at ameliorating some ofthe symptoms of the CNS disorders leads to alterations ofthe calcineurin expression pattern in the human brain [249ndash253] Decreased calcineurin levels in the nucleus accum-bens were reported in opioid withdrawal a dysphoric stateassociated with complications in patient pain and increasedrisk of drug abuse and addiction [30] suggesting a rolefor calcineurin in long-lasting behaviors associated withreward Furthermore in a patch-clamp electrophysiology andfast-scan cyclic voltammetry study in mouse brain slicesthe endogenous modulatory peptide neurotensin induced along-term prevention of pathogenic increases in presynapticdopamine release characteristic of schizophrenia and othersevere mesencephalic pathologies by increasing inhibitoryD2 dopamine autoreceptor function via a calcineurin-dependent mechanism [35]

523 Epilepsy Many lines of evidence also support cal-cineurin involvement in nervous system diseases Notablyvarious reports have suggested that calcineurin is likely tomediate physiological and pathological activities of GABAreceptors For instance complex interactions between PKCand calcineurin may play a key role in GABA B autoreceptor-mediated functional regulation of nicotinic acetylcholinereceptors (nAChRs) whose activation triggers the releaseof neurotransmitters from presynaptic nerve terminals inmouse striatal GABAergic nerve terminals [254] Somaticmodulation of GABA A receptor-mediated fast inhibitorysignaling in epileptiform activity was induced by calcineurinsignaling in low-magnesium model of seizure in rat hip-pocampal neurons [31] suggesting a role of calcineurin inbenzodiazepine resistance and the potential of its pharmaco-logical targeting in status epilepticus

Certainly calcineurinNFAT signaling involvement wasalso shown in pathogenic processes of other models ofstatus epilepticus including intracerebral injection of kainicacid [255] bicuculline [256] and pilocarpine [33] Notablycalcineurin inhibitor ascomycin mediated anticonvulsantand neuroprotective effects in different epilepsy modelsincluding picrotoxin and latrunculin A models [257ndash259]

53 Emerging Challenge Better Models A growing numberof studies are raising concerns about mechanistic reports ofCa2+-dependent and other signaling pathways from currentlyused models of neurodegenerative diseases in particulartransgenic animals and cell lines A study addressing thesuitability of rat striatal primordia-derived ST14A cell line forthe study of voltage-gated Ca2+ channel of striatal mediumspiny neurons called for serious caution on the assumptionof the presence of complete signaling cascades of G-protein


coupled receptors in cell lines [260] Notably ST14A cellswere reported to lack PLC-1205731 a major effector of G-proteinsfor Ca2+ release from intracellular stores [59 82] whose rolesinclude (i) the regulation of forward locomotion in wild-typemice among other dopamine receptor functions [261] (ii)the mediation of Ca2+ flux required for mammalian spermacrosome reaction [262] and (iii) the mediation of the posi-tive regulation of osteoblast differentiation [263] In additionmost observations from studies in preclinical models of neu-rodegenerative diseases based on exogenous neurotoxins arenot confirmed by clinical studies [264ndash266] Similar observa-tions emerge from studies in transgenic animals where com-plex functional adaptations from gene knock-in or knock-outmay limit the translational importance of findings [267ndash269]In the case of neurodegenerative conditions at least someof the controversy regarding changes in calcineurinNFATactivity andor expression appears to be due to the method-ologies employed to measure activities and expression levelsCalcineurin in particular is highly sensitive to proteoly-sis during injury and neurodegeneration However mostcommercial antibodies to calcineurin only detect full-lengthcalcineurin andmiss the detection of high activity proteolyticfragments Also many studies have tended to measurecalcineurin activity in whole brain tissue homogenates usingcommercially available phosphatase assaysWhile these kindsof assays are very good for kinetic analyses they are verypoor at assessing endogenous calcineurin activity towardendogenous substrates Certainly methodological challengesmay have affected the quality of data generated by differentgroups Although it appears that bettermodels are needed wealso propose that better characterization of intracellular sig-naling in currently available and future experimental modelsmay improve the translational importance of the findings

6 Concluding Remarks

CalcineurinNFAT pathway is pivotal during nervous systemdevelopment and in various functions of mature central andperipheral nervous system Notably this signaling pathwayis involved in myelination corticogenesis synaptogenesisneuritogenesis endosome trafficking homeostatic synapticplasticity learning and memory Experimental evidence alsoshows that alterations in the activity of calcineurinNFATpathway and in activities of its endogenous regulators in thenervous system microvascular endothelial cells astrocytesmicroglia Schwann cells oligodendrocytes and neuronsparticipate in the pathogenesis of neurodegenerative dis-eases and conditions but also psychotic disorders Stud-ies in transgenic animals and in cell lines also suggestedthat neurodegeneration-associated detrimental changes incalcineurinNFAT signaling are NFAT isoform-selective aschanges in NFATc3 and NFATc4 but not NFATc1 or NFATc2are usually common In addition pharmacological inhibitionmitigated neuronal and astrocyte loss and improved cognitivefunctions in many models However other studies reportedbeneficial roles of calcineurinNFAT in neurodegenerativediseases and conditions in particular those reporting neu-rotoxic effects of pharmacological inhibition and increased

endogenous regulation These studies suggested that cal-cineurin can mediate both neuroprotective and neurodegen-erative signals according to poorly understood determinantfactors which included the activation status of astrocytes inthe central nervous system Future studies should be devisedto characterize better the factors determining the outcomeof calcineurinNFAT signaling in neurodegenerative diseasesand conditions as well as the downstream targets mediatingthe beneficial and detrimental effects of this signaling path-way considering the implications for therapy

Competing Interests

Authors have no conflict of interests

References

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[2] A M Cardenas and F D Marengo ldquoHow the stimulus definesthe dynamics of vesicle pool recruitment fusion mode andvesicle recycling in neuroendocrine cellsrdquo Journal of Neuro-chemistry vol 137 no 6 pp 867ndash879 2016

[3] M Buchholz and V Ellenrieder ldquoAn emerging role for Ca2+calcineurinNFAT signaling in cancerogenesisrdquo Cell Cycle vol6 no 1 pp 16ndash19 2007

[4] A Gafter-Gvili B Sredni R Gal U Gafter and Y KalechmanldquoCyclosporin A-induced hair growth in mice is associatedwith inhibition of calcineurin-dependent activation of NFAT infollicular keratinocytesrdquo American Journal of PhysiologymdashCellPhysiology vol 284 no 6 pp C1593ndashC1603 2003

[5] I A Graef F Chen L Chen A Kuo and G R Crabtree ldquoSig-nals transduced byCa2+calcineurin andNFATc3c4 pattern thedeveloping vasculaturerdquo Cell vol 105 no 7 pp 863ndash875 2001

[6] J J Heit A A Apelqvist X Gu et al ldquoCalcineurinNFATsignalling regulates pancreatic 120573-cell growth and functionrdquoNature vol 443 no 7109 pp 345ndash349 2006

[7] V Horsley A O Aliprantis L Polak L H Glimcher and EFuchs ldquoNFATc1 balances quiescence and proliferation of skinstem cellsrdquo Cell vol 132 no 2 pp 299ndash310 2008

[8] S-C Kao H Wu J Xie et al ldquoCalcineurinNFAT signaling isrequired for neuregulin-regulated Schwann cell differentiationrdquoScience vol 323 no 5914 pp 651ndash654 2009

[9] M J Kipanyula A Woodhoo M Rahman D Payne K RJessen and RMirsky ldquoCalcineurin-nuclear factor of activated tcells regulation of Krox-20 expression in Schwann cells requireselevation of intracellular cyclic AMPrdquo Journal of NeuroscienceResearch vol 91 no 1 pp 105ndash115 2013

[10] M C Lawrence N Borenstein-Auerbach K McGlynn et alldquoNFAT targets signaling molecules to gene promoters in pan-creatic 120573-cellsrdquoMolecular Endocrinology vol 29 no 2 pp 274ndash288 2015

[11] C Mammucari A T D Vignano A A Sharov et al ldquoIntegra-tion of Notch 1 and calcineurinNFAT signaling pathways inkeratinocyte growth anddifferentiation controlrdquoDevelopmentalCell vol 8 no 5 pp 665ndash676 2005

[12] X-S Wu Z Zhang W-D Zhao D Wang F Luo and L-GWu ldquoCalcineurin is universally involved in vesicle endocytosisat neuronal and nonneuronal secretory cellsrdquo Cell Reports vol7 no 4 pp 982ndash988 2014


[13] J C Braz O F Bueno Q Liang et al ldquoTargeted inhibitionof p38MAPK promotes hypertrophic cardiomyopathy throughupregulation of calcineurin-NFAT signalingrdquo The Journal ofClinical Investigation vol 111 no 10 pp 1475ndash1486 2003

[14] G R Crabtree and E N Olson ldquoNFAT signaling choreograph-ing the social lives of cellsrdquo Cell vol 109 no 2 supplement 1pp S67ndashS79 2002

[15] T Minami S Jiang K Schadler et al ldquoThe calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical forthe establishment of lung metastasesrdquo Cell Reports vol 4 no 4pp 709ndash723 2013

[16] E N Olson and R S Williams ldquoCalcineurin signaling andmuscle remodelingrdquo Cell vol 101 no 7 pp 689ndash692 2000

[17] B Pyrzynska A Lis G Mosieniak and B Kaminska ldquoCyclo-sporin A-sensitive signaling pathway involving calcineurinregulates survival of reactive astrocytesrdquo Neurochemistry Inter-national vol 38 no 5 pp 409ndash415 2001

[18] R P Sah R K Dawra and A K Saluja ldquoNew insights into thepathogenesis of pancreatitisrdquo Current Opinion in Gastroenterol-ogy vol 29 no 5 pp 523ndash530 2013

[19] B Artegiani A M de Jesus Domingues S Bragado Alonsoet al ldquoTox a multifunctional transcription factor and novelregulator of mammalian corticogenesisrdquo The EMBO Journalvol 34 no 7 pp 896ndash910 2015

[20] M Fukuchi A Tabuchi Y Kuwana et al ldquoNeuromodulatoryeffect of G120572s- or G120572q-coupled G-protein-coupled receptor onNMDA receptor selectively activates theNMDA receptorCa2+calcineurincAMP response element-binding protein-regulatedtranscriptional coactivator 1 pathway to effectively inducebrain-derived neurotrophic factor expression in neuronsrdquo TheJournal of Neuroscience vol 35 no 14 pp 5606ndash5624 2015

[21] S Sawamura M Hatano Y Takada et al ldquoScreening of tran-sient receptor potential canonical channel activators identifiesnovel neurotrophic piperazine compoundsrdquo Molecular Phar-macology vol 89 no 3 pp 348ndash363 2016

[22] M C Serrano-Perez M Fernandez F Neria et al ldquoNFATtranscription factors regulate survival proliferation migrationand differentiation of neural precursor cellsrdquoGlia vol 63 no 6pp 987ndash1004 2015

[23] M Tsuda ldquoGene regulation involved in the formation of long-term memoryrdquo Yakugaku Zasshi vol 135 no 4 pp 597ndash6172015

[24] D Dubey and B E Porter ldquoCRTC1 nuclear localization inthe hippocampus of the pilocarpine-induced status epilepticusmodel of temporal lobe epilepsyrdquoNeuroscience vol 320 pp 43ndash56 2016

[25] S Kim C J Violette and E B Ziff ldquoReduction of increasedcalcineurin activity rescues impaired homeostatic synapticplasticity in presenilin 1 M146VmutantrdquoNeurobiology of Agingvol 36 no 12 pp 3239ndash3246 2015

[26] B Mojsa S Mora J P Bossowski I Lassot and S DesagherldquoControl of neuronal apoptosis by reciprocal regulation ofNFATc3 and Trim17rdquo Cell Death and Differentiation vol 22 no2 pp 274ndash286 2015

[27] T Boczek B Ferenc M Lisek and L Zylinska ldquoRegulationof GAP43calmodulin complex formation via calcineurin-dependent mechanism in differentiated PC12 cells with alteredPMCA isoforms compositionrdquoMolecular andCellular Biochem-istry vol 407 no 1-2 pp 251ndash262 2015

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[29] A P Spira C E Gonzalez V K Venkatraman et al ldquoSleepduration and subsequent cortical thinning in cognitively nor-mal older adultsrdquo Sleep vol 39 no 5 pp 1121ndash1128 2016

[30] E M Anderson T Reeves K Kapernaros J K Neubert andR M Caudle ldquoPhosphorylation of the N-methyl-d-aspartatereceptor is increased in the nucleus accumbens during bothacute and extended morphine withdrawalrdquo Journal of Pharma-cology and Experimental Therapeutics vol 355 no 3 pp 496ndash505 2015

[31] R Eckel B Szulc M C Walker and J T Kittler ldquoActivation ofcalcineurin underlies altered trafficking of 1205722 subunit contain-ing GABAA receptors during prolonged epileptiform activityrdquoNeuropharmacology vol 88 pp 82ndash90 2015

[32] G Li W Yan Y Dang J Li C Liu and J Wang ldquoThe roleof calcineurin signaling in microcystin-LR triggered neuronaltoxicityrdquo Scientific Reports vol 5 Article ID 11271 2015

[33] J Liu X Li L Chen P Xue Q Yang and A Wang ldquoIncreasedcalcineurin expression after pilocarpine-induced status epilep-ticus is associated with brain focal edema and astrogliosisrdquoInternational Journal of Neuroscience vol 126 no 6 pp 560ndash567 2016

[34] A Madineni Q Alhadidi and Z A Shah ldquoCofilin inhibitionrestores neuronal cell death in oxygen-glucose deprivationmodel of ischemiardquo Molecular Neurobiology vol 53 no 2 pp867ndash878 2016

[35] E Piccart N A Courtney S Y Branch C P Ford andM J Beckstead ldquoNeurotensin induces presynaptic depressionof D2dopamine autoreceptor-mediated neurotransmission in

midbrain dopaminergic neuronsrdquo Journal of Neuroscience vol35 no 31 pp 11144ndash11152 2015

[36] Z Mei P Yan X Tan S Zheng and B Situ ldquoTranscriptionalregulation of BACE1 by NFAT3 leads to enhanced amyloido-genic processingrdquo Neurochemical Research vol 40 no 4 pp829ndash836 2015

[37] H Vihma M Luhakooder P Pruunsild and T TimmuskldquoRegulation of different human NFAT isoforms by neuronalactivityrdquo Journal of Neurochemistry vol 137 no 3 pp 394ndash4082016

[38] L-J Chen Y-J Wang J-R Chen and G-F Tseng ldquoNMDAreceptor triggered molecular cascade underlies compression-induced rapid dendritic spine plasticity in cortical neuronsrdquoExperimental Neurology vol 266 pp 86ndash98 2015

[39] J L Furman P Sompol S D Kraner et al ldquoBlockade ofastrocytic calcineurinNFAT signaling helps to normalize hip-pocampal synaptic function and plasticity in a rat model oftraumatic brain injuryrdquoThe Journal of Neuroscience vol 36 no5 pp 1502ndash1515 2016

[40] K J Gan and M A Silverman ldquoDendritic and axonalmechanisms of Ca2+ elevation impair BDNF transport in A120573oligomer-treated hippocampal neuronsrdquo Molecular Biology ofthe Cell vol 26 no 6 pp 1058ndash1071 2015

[41] MGratuze A Noel C Julien et al ldquoTau hyperphosphorylationand deregulation of calcineurin inmousemodels of Hunting-tonrsquos diseaserdquo Human Molecular Genetics vol 24 no 1 pp 86ndash99 2015

[42] H C Ho T S Teo R Desai and J H Wang ldquoCatalyticand regulatory properties of two forms of bovine heart cyclicnucleotide phosphodiesteraserdquo Biochimica et Biophysica Acta(BBA)mdashEnzymology vol 429 no 2 pp 461ndash473 1976


[43] J H Wang and R Desai ldquoA brain protein and its effect on theCA2+-and protein modulator-activated cyclic nucleotide phos-phodiesteraserdquo Biochemical and Biophysical Research Commu-nications vol 72 no 3 pp 926ndash932 1976

[44] H Li A Rao and P G Hogan ldquoInteraction of calcineurin withsubstrates and targeting proteinsrdquo Trends in Cell Biology vol 21no 2 pp 91ndash103 2011

[45] F Rusnak and P Mertz ldquoCalcineurin form and functionrdquoPhysiological Reviews vol 80 no 4 pp 1483ndash1521 2000

[46] F Mathieu S Miot B Etain et al ldquoAssociation between thePPP3CC gene coding for the calcineurin gamma catalyticsubunit and bipolar disorderrdquo Behavioral and Brain Functionsvol 4 article 2 2008

[47] C R Williams and J L Gooch ldquoCalcineurin inhibitors andimmunosuppressionmdasha tale of two isoformsrdquo Expert Reviews inMolecular Medicine vol 14 article e14 2012

[48] R J Bram D T Hung P K Martin S L Schreiber and GR Crabtree ldquoIdentification of the immunophilins capable ofmediating inhibition of signal transduction by cyclosporin Aand FK506 roles of calcineurin binding and cellular locationrdquoMolecular and Cellular Biology vol 13 no 8 pp 4760ndash47691993

[49] N Usuda H Arai H Sasaki et al ldquoDifferential subcellularlocalization of neural isoforms of the catalytic subunit ofcalmodulin-dependent protein phosphatase (calcineurin) incentral nervous system neurons immunohistochemistry onformalin-fixed paraffin sections employing antigen retrieval bymicrowave irradiationrdquo Journal of Histochemistry and Cyto-chemistry vol 44 no 1 pp 13ndash18 1996

[50] S Mehta N-N Aye-Han A Ganesan L Oldach K Gorshkovand J Zhang ldquoCalmodulin-controlled spatial decoding ofoscillatory Ca2+ signals by calcineurinrdquo eLife vol 3 articlee03765 2014

[51] S Mehta and J Zhang ldquoUsing a genetically encoded FRET-based reporter to visualize calcineurin phosphatase activity inliving cellsrdquoMethods inMolecular Biology vol 1071 pp 139ndash1492014

[52] FAAnthonyMAWinklerHH Edwards andWYCheungldquoQuantitative subcellular localization of calmodulin-dependentphosphatase in chick forebrainrdquo The Journal of Neurosciencevol 8 no 4 pp 1245ndash1253 1988

[53] M Boothby ldquoCracking the code without rosetta molecularregulation of calcium-stimulated gene transcription after T cellactivationrdquoThe Journal of Immunology vol 185 no 9 pp 4969ndash4971 2010

[54] R A Schulz and K E Yutzey ldquoCalcineurin signaling and NFATactivation in cardiovascular and skeletal muscle developmentrdquoDevelopmental Biology vol 266 no 1 pp 1ndash16 2004

[55] J-P Shaw P J Utz D B Durand J J Toole E A Emmel andG R Crabtree ldquoIdentification of a putative regulator of early Tcell activation genesrdquo Journal of Immunology vol 185 no 9 pp4972ndash4975 2010

[56] H Vihma P Pruunsild and T Timmusk ldquoAlternative splicingand expression of human and mouse NFAT genesrdquo Genomicsvol 92 no 5 pp 279ndash291 2008

[57] L Jin P Sliz L Chen et al ldquoAn asymmetric NFAT1 dimeron a pseudo-palindromic 120581B-like DNA siterdquo Nature StructuralBiology vol 10 no 10 pp 807ndash811 2003

[58] J Aramburu F Garcıa-Cozar A Raghavan H Okamura ARao and P G Hogan ldquoSelective inhibition of NFAT activationby a peptide spanning the calcineurin targeting site of NFATrdquoMolecular Cell vol 1 no 5 pp 627ndash637 1998

[59] M R Muller Y Sasaki I Stevanovic et al ldquoRequirement forbalanced CaNFAT signaling in hematopoietic and embryonicdevelopmentrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 106 no 17 pp 7034ndash70392009

[60] Z Qian P G Dougherty T Liu et al ldquoStructure-basedoptimization of a peptidyl inhibitor against calcineurin-nuclearfactor of activated T cell (NFAT) interactionrdquo Journal of Medic-inal Chemistry vol 57 no 18 pp 7792ndash7797 2014

[61] Q Wang Y Zhou P Rychahou C Liu H L Weiss and B MEvers ldquoNFAT5 represses canonical Wnt signaling via inhibitionof 120573-catenin acetylation and participates in regulating intestinalcell differentiationrdquo Cell Death and Disease vol 4 article e6712013

[62] D V Faget P I Lucena B K Robbs and J P B ViolaldquoNFAT1 C-terminal domains are necessary but not sufficient forinducing cell deathrdquo PLoS ONE vol 7 no 10 article e478682012

[63] M De Lumley D J Hart M A Cooper S Symeonidesand J M Blackburn ldquoA biophysical characterisation of factorscontrolling dimerisation and selectivity in theNF-120581B andNFATfamiliesrdquo Journal of Molecular Biology vol 339 no 5 pp 1059ndash1075 2004

[64] S A Wolfe P Zhou V Dotsch et al ldquoUnusual rel-likearchitecture in the DNA-binding domain of the transcriptionfactor NFATcrdquo Nature vol 385 no 6612 pp 172ndash176 1997

[65] D L Bates K K B Barthel Y Wu et al ldquoCrystal structure ofNFAT bound to the HIV-1 LTR tandem 120581B enhancer elementrdquoStructure vol 16 no 5 pp 684ndash694 2008

[66] C-H Chen V A Martin N M Gorenstein R L Geahlenand C B Post ldquoTwo closely spaced tyrosines regulate NFATsignaling in B cells via Syk association with VavrdquoMolecular andCellular Biology vol 31 no 14 pp 2984ndash2996 2011

[67] E Dirkx M M Gladka L E Philippen et al ldquoNfat and miR-25cooperate to reactivate the transcription factor Hand2 in heartfailurerdquo Nature Cell Biology vol 15 no 11 pp 1282ndash1293 2013

[68] H Hu I Djuretic M S Sundrud and A Rao ldquoTranscriptionalpartners in regulatory T cells Foxp3 Runx and NFATrdquo Trendsin Immunology vol 28 no 8 pp 329ndash332 2007

[69] S-H Im and A Rao ldquoActivation and deactivation of geneexpression by Ca2+calcineurin-NFAT-mediated signalingrdquoMolecules and Cells vol 18 no 1 pp 1ndash9 2004

[70] F Macian C Lopez-Rodrıguez and A Rao ldquoPartners intranscription NFAT and AP-1rdquo Oncogene vol 20 no 19 pp2476ndash2489 2001

[71] K Park J-H Park W-J Yang J-J Lee M-J Song and H-PKim ldquoTranscriptional activation of the IL31 gene by NFAT andSTAT6rdquo Journal of Leukocyte Biology vol 91 no 2 pp 245ndash2572012

[72] Y J Shyu C D Suarez and C-D Hu ldquoVisualization of AP-1-NF-120581B ternary complexes in living cells by using a BiFC-basedFRETrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 1 pp 151ndash156 2008

[73] W Wang J Lou R Zhong et al ldquoThe roles of Ca2+NFATsignaling genes in kawasaki disease single-and multiple-riskgenetic variantsrdquo Scientific Reports vol 4 article 5208 2014

[74] J Zuo F Wu Y Liu et al ldquoMicroRNA transcriptome profileanalysis in porcine muscle and the effect of miR-143 on theMYH7 gene and proteinrdquo PLoS ONE vol 10 no 4 Article IDe0124873 2015


[75] I A Graef F Wang F Charron et al ldquoNeurotrophins andnetrins require calcineurinNFAT signaling to stimulate out-growth of embryonic axonsrdquo Cell vol 113 no 5 pp 657ndash6702003

[76] G L Hernandez O V Volpert M A Iniguez et al ldquoSelec-tive inhibition of vascular endothelial growth factor-mediatedangiogenesis by cyclosporin A roles of the nuclear factor ofactivated T cells and cyclooxygenase 2rdquo Journal of ExperimentalMedicine vol 193 no 5 pp 607ndash620 2001

[77] M-S Kim L P Shutov A Gnanasekaran et al ldquoNerve growthfactor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase(PI3K)-Akt-glycogen synthase kinase 3120573 (GSK3120573) pathwayrdquoThe Journal of Biological Chemistry vol 289 no 45 pp 31349ndash31360 2014

[78] E H Y Tong J-J Guo S-X Xu et al ldquoInducible nucleosomedepletion at OREBP-binding-sites by hypertonic stressrdquo PLoSONE vol 4 no 12 article e8435 2009

[79] A Canellada B G Ramirez T Minami J M Redondo and ECano ldquoCalciumcalcineurin signaling in primary cortical astro-cyte cultures Rcan1-4 and cyclooxygenase-2 as NFAT targetgenesrdquo Glia vol 56 no 7 pp 709ndash722 2008

[80] V Horsley and G K Pavlath ldquoNFAT ubiquitous regulator ofcell differentiation and adaptationrdquo Journal of Cell Biology vol156 no 5 pp 771ndash774 2002

[81] S Reppert E Zinser C Holzinger L Sandrock S Kochand S Finotto ldquoNFATc1 deficiency in T cells protects micefrom experimental autoimmune encephalomyelitisrdquo EuropeanJournal of Immunology vol 45 no 5 pp 1426ndash1440 2015

[82] D Park D-Y Jhon C-W Lee K-H Lee and S G RheeldquoActivation of phospholipase C isozymes by G protein 120573120574subunitsrdquo The Journal of Biological Chemistry vol 268 no 7pp 4573ndash4576 1993

[83] D Mandikian E Bocksteins L K Parajuli et al ldquoCell type-specific spatial and functional coupling between mammalianbrain Kv21 K+ channels and ryanodine receptorsrdquo Journal ofComparative Neurology vol 522 no 15 pp 3555ndash3574 2014

[84] F J Munoz J A GodoyW Cerpa I M Poblete J P Huidobro-Toro andN C Inestrosa ldquoWnt-5a increases NO andmodulatesNMDA receptor in rat hippocampal neuronsrdquo Biochemical andBiophysical Research Communications vol 444 no 2 pp 189ndash194 2014

[85] W C Oh L K Parajuli and K Zito ldquoHeterosynaptic structuralplasticity on local dendritic segments of hippocampal CA1neuronsrdquo Cell Reports vol 10 no 2 pp 162ndash169 2015

[86] T Vervliet J B Parys andG Bultynck ldquoBcl-2 and FKBP12 bindto IP3and ryanodine receptors at overlapping sites the com-

plexity of protein-protein interactions for channel regulationrdquoBiochemical Society Transactions vol 43 pp 396ndash404 2015

[87] Y Yamazaki S Fujii J-I Goto H Fujiwara and K MikoshibaldquoActivation of inositol 145-trisphosphate receptors duringpreconditioning low-frequency stimulation suppresses subse-quent induction of long-term potentiation in hippocampal CA1neuronsrdquo Neuroscience vol 311 pp 195ndash206 2015

[88] H Okamura J Aramburu C Garcıa-Rodrıguez et al ldquoCon-certed dephosphorylation of the transcription factor NFAT1induces a conformational switch that regulates transcriptionalactivityrdquoMolecular Cell vol 6 no 3 pp 539ndash550 2000

[89] Z-H Deng T S Gomez D G Osborne C A Phillips-Krawczak J-S Zhang and D D Billadeau ldquoNuclear FAM21participates in NF-120581B-dependent gene regulation in pancreatic

cancer cellsrdquo Journal of Cell Science vol 128 no 2 pp 373ndash3842015

[90] R S Lewis ldquoCalcium oscillations in T-cells mechanisms andconsequences for gene expressionrdquo Biochemical Society Trans-actions vol 31 no 5 pp 925ndash929 2003

[91] A N Mitchell L Jayakumar I Koleilat et al ldquoBrain expressionof the calcineurin inhibitor RCAN1 (Adapt78)rdquo Archives ofBiochemistry and Biophysics vol 467 no 2 pp 185ndash192 2007

[92] A Patel N YamashitaM Ascano et al ldquoRCAN1 links impairedneurotrophin trafficking to aberrant development of thesympathetic nervous system in Down syndromerdquo Nature Com-munications vol 6 Article ID 10119 2015

[93] P G Hogan L Chen J Nardone and A Rao ldquoTranscriptionalregulation by calcium calcineurin and NFATrdquo Genes andDevelopment vol 17 no 18 pp 2205ndash2232 2003

[94] E Kilanczyk A Filipek and M Hetman ldquoCalcyclin-bindingproteinSiah-1-interacting protein as a regulator of transcrip-tional responses in brain cellsrdquo Journal of Neuroscience Researchvol 93 no 1 pp 75ndash81 2015

[95] P G Del Arco S Martınez-Martınez J L Maldonado IOrtega-Perez and J M Redondo ldquoA role for the p38 MAPkinase pathway in the nuclear shuttling of NFATprdquo Journal ofBiological Chemistry vol 275 no 18 pp 13872ndash13878 2000

[96] P J Dittmer M L DellrsquoAcqua and W A Sather ldquoCa2+calcineurin-dependent inactivation of neuronal L-type Ca2+channels requires priming by AKAP-anchored protein kinaseArdquo Cell Reports vol 7 no 5 pp 1410ndash1416 2014

[97] B K Samelson B B Gore J LWhiting et al ldquoA-kinase anchor-ing protein 79150 recruits protein kinase C to phosphorylateroundabout receptorsrdquoThe Journal of Biological Chemistry vol290 no 22 pp 14107ndash14119 2015

[98] Y Wen P Zhou L Liu Z Wang Y Zhang and J Liang ldquoEffectof the knockdown of Cabin1 on p53 in glomerular podocyterdquoJournal of Receptors and Signal Transduction vol 36 no 2 pp173ndash180 2016

[99] J-K Yi H-J Kim D-H Yu et al ldquoRegulation of inflam-matory responses and fibroblast-like synoviocyte apoptosis bycalcineurin-binding protein 1 in mice with collagen-inducedarthritisrdquo Arthritis and Rheumatism vol 64 no 7 pp 2191ndash2200 2012

[100] FDi Sole KVadnagaraOWMoe andV Babich ldquoCalcineurinhomologous protein a multifunctional Ca2+-binding proteinfamilyrdquo American Journal of PhysiologymdashRenal Physiology vol303 no 2 pp F165ndashF179 2012

[101] Y Kobayashi R da Silva H Kumanogoh et al ldquoGangliosidecontained in the neuronal tissue-enriched acidic protein of 22kDa (NAP-22) fraction prepared from the detergent-resistantmembrane microdomain of rat brain inhibits the phosphataseactivity of calcineurinrdquo Journal of Neuroscience Research vol 93no 9 pp 1462ndash1470 2015

[102] X Lin R A Sikkink F Rusnak and D L Barber ldquoInhibition ofcalcineurin phosphatase activity by a calcineurin B homologousproteinrdquoThe Journal of Biological Chemistry vol 274 no 51 pp36125ndash36131 1999

[103] R B Vega J Yang B A Rothermel R Bassel-Duby and R SWilliams ldquoMultiple domains of MCIP1 contribute to inhibitionof calcineurin activityrdquo Journal of Biological Chemistry vol 277no 33 pp 30401ndash30407 2002

[104] C Brandt V Pavlovic A Radbruch M Worm and RBaumgrass ldquoLow-dose cyclosporine A therapy increases theregulatory T cell population in patients with atopic dermatitisrdquoAllergy vol 64 no 11 pp 1588ndash1596 2009


[105] J Cury Martins C Martins V Aoki A F T Gois H A Ishiiand EM K da Silva ldquoTopical tacrolimus for atopic dermatitisrdquoThe Cochrane Database of Systematic Reviews no 7 Article IDCD009864 2015

[106] B Hocker and B Tonshoff ldquoCalcineurin inhibitor-free immu-nosuppression in pediatric renal transplantation a viableoptionrdquo Pediatric Drugs vol 13 no 1 pp 49ndash69 2011

[107] J M Tredger N W Brown and A Dhawan ldquoCalcineurininhibitor sparing in paediatric solid organ transplantationmanaging the efficacytoxicity conundrumrdquo Drugs vol 68 no10 pp 1385ndash1414 2008

[108] B Kaminska I Figiel B Pyrzynska R Czajkowski and GMosieniak ldquoTreatment of hippocampal neurons with cyclo-sporin A results in calcium overload and apoptosis which areindependent on NMDA receptor activationrdquo British Journal ofPharmacology vol 133 no 7 pp 997ndash1004 2001

[109] J Klawitter S Gottschalk C Hainz D Leibfritz U Christiansand N J Serkova ldquoImmunosuppressant neurotoxicity in ratbrain models oxidative stress and cellular metabolismrdquo Chem-ical Research in Toxicology vol 23 no 3 pp 608ndash619 2010

[110] R Gomez-Sintes and J J Lucas ldquoNFATFas signaling mediatesthe neuronal apoptosis and motor side effects of GSK-3 inhibi-tion in amousemodel of lithium therapyrdquoTheJournal of ClinicalInvestigation vol 120 no 7 pp 2432ndash2445 2010

[111] L Bica J R Liddell P S Donnelly et al ldquoNeuroprotectivecopper bis(thiosemicarbazonato) complexes promote neuriteelongationrdquo PLoS ONE vol 9 no 2 Article ID e90070 2014

[112] T Johanssen N Suphantarida P S Donnelly et al ldquoPBT2inhibits glutamate-induced excitotoxicity in neurons throughmetal-mediated preconditioningrdquo Neurobiology of Disease vol81 pp 176ndash185 2015

[113] F Rapisarda G Portale S Ferrario et al ldquoMagnesium calciumand potassium lsquono one was born alonersquordquo Giornale Italiano diNefrologia vol 33 2016

[114] S-R Chen Y-M Hu H Chen and H-L Pan ldquoCalcineurininhibitor induces pain hypersensitivity by potentiating pre- andpostsynaptic NMDA receptor activity in spinal cordsrdquo Journalof Physiology vol 592 no 1 pp 215ndash227 2014

[115] S-R Chen H-Y Zhou H S Byun H Chen and H-LPan ldquoCasein kinase II regulates N-methyl-d-aspartate receptoractivity in spinal cords and pain hypersensitivity induced bynerve injuryrdquo The Journal of Pharmacology and ExperimentalTherapeutics vol 350 no 2 pp 301ndash312 2014

[116] G Miletic J L Hermes G L Bosscher B M Meier and VMiletic ldquoProtein kinaseC gamma-mediated phosphorylation ofGluA1 in the postsynaptic density of spinal dorsal horn neuronsaccompanies neuropathic pain and dephosphorylation by cal-cineurin is associated with prolonged analgesiardquo PAIN vol 156no 12 pp 2514ndash2520 2015

[117] Y-MHu S-R Chen H Chen andH-L Pan ldquoCasein kinase IIinhibition reverses pain hypersensitivity and potentiated spinalN-methyl-D-aspartate receptor activity caused by calcineurininhibitorrdquo Journal of Pharmacology and ExperimentalTherapeu-tics vol 349 no 2 pp 239ndash247 2014

[118] H J Solinski F Petermann K Rothe I Boekhoff T Guder-mann and A Breit ldquoHuman Mas-related G protein-coupledreceptors-X1 induce chemokine receptor 2 expression in ratdorsal root ganglia neurons and release of chemokine ligand 2from the human LAD-2 mast cell linerdquo PLoS ONE vol 8 no 3Article ID e58756 2013

[119] M H A Roehrl J Y Wang and G Wagner ldquoDiscoveryof small-molecule inhibitors of the NFAT-calcineurin interac-tion by competitive high-throughput fluorescence polarizationscreeningrdquo Biochemistry vol 43 no 51 pp 16067ndash16075 2004

[120] K Takeuchi M H A Roehrl Z-Y J Sun and G WagnerldquoStructure of the calcineurin-NFAT complex defining a T cellactivation switch using solution NMR and crystal coordinatesrdquoStructure vol 15 no 5 pp 587ndash597 2007

[121] B Ding W Wang T Selvakumar et al ldquoTemporal regulationof nuclear factor one occupancy by calcineurinNFAT governsa voltage-sensitive developmental switch in late maturing neu-ronsrdquoThe Journal of Neuroscience vol 33 no 7 pp 2860ndash28722013

[122] A Cho Y Tang J Davila et al ldquoCalcineurin signaling regulatesneural induction through antagonizing the BMP pathwayrdquoNeuron vol 82 no 1 pp 109ndash124 2014

[123] M D Cahalan ldquoSTIMulating store-operated Ca2+ entryrdquoNature Cell Biology vol 11 no 6 pp 669ndash677 2009

[124] R Palty A Raveh I Kaminsky R Meller and E ReuvenyldquoSARAF inactivates the store operated calcium entrymachineryto prevent excess calcium refillingrdquo Cell vol 149 no 2 pp 425ndash438 2012

[125] A Somasundaram A K Shum H J McBride et al ldquoStore-operated CRAC channels regulate gene expression and prolif-eration in neural progenitor cellsrdquoThe Journal of Neurosciencevol 34 no 27 pp 9107ndash9123 2014

[126] J D UlrichM-S Kim P RHoulihan et al ldquoDistinct activationproperties of the nuclear factor of activated T-cells (NFAT)isoforms NFATc3 and NFATc4 in neuronsrdquo Journal of BiologicalChemistry vol 287 no 45 pp 37594ndash37609 2012

[127] J A Filosa M T Nelson and L V Gonzalez BoscldquoActivity-dependent NFATc3 nuclear accumulation in pericytesfrom cortical parenchymal microvesselsrdquo American Journal ofPhysiologymdashCell Physiology vol 293 no 6 pp C1797ndashC18052007

[128] H Q Yan S S Shin X Ma Y Li and C E Dixon ldquoDifferentialeffect of traumatic brain injury on the nuclear factor of activatedT Cells C3 and C4 isoforms in the rat hippocampusrdquo BrainResearch vol 1548 pp 63ndash72 2014

[129] M Fukuchi Y Kirikoshi A Mori et al ldquoExcitatory GABAinduces BDNF transcription via CRTC1 and phosphorylatedCREB-related pathways in immature cortical cellsrdquo Journal ofNeurochemistry vol 131 no 2 pp 134ndash146 2014

[130] F Niwa H Bannai M Arizono K Fukatsu A Triller andK Mikoshiba ldquoGephyrin-independent GABAAR mobility andclustering during plasticityrdquo PLoS ONE vol 7 no 4 Article IDe36148 2012

[131] G C Stefos U Soppa M Dierssen and W Becker ldquoNGFupregulates the plasminogen activation inhibitor-1 in neuronsvia the calcineurinNFAT pathway and the Down syndrome-related proteins DYRK1A and RCAN1 attenuate this effectrdquoPLoS ONE vol 8 no 6 Article ID e67470 2013

[132] C-Y Wang H-C Lin Y-P Song et al ldquoProtein kinase C-dependent growth-associated protein 43 phosphorylation regu-lates gephyrin aggregation at developing GABAergic synapsesrdquoMolecular and Cellular Biology vol 35 no 10 pp 1712ndash17262015

[133] F J Caballero R Soler-Torronteras M Lara-Chica et alldquoAM404 inhibits NFAT and NF-120581B signaling pathways andimpairs migration and invasiveness of neuroblastoma cellsrdquoEuropean Journal of Pharmacology vol 746 pp 221ndash232 2015


[134] A E Chavez V M Hernandez A Rodenas-Ruano C SavioChan and P E Castillo ldquoCompartment-specific modulation ofGABAergic synaptic transmission by TRPV1 channels in thedentate gyrusrdquo The Journal of Neuroscience vol 34 no 50 pp16621ndash16629 2014

[135] T Hayama J Noguchi S Watanabe et al ldquoGABA promotesthe competitive selection of dendritic spines by controlling localCa2+ signalingrdquo Nature Neuroscience vol 16 no 10 pp 1409ndash1416 2013

[136] H Toyoda M Saito H Sato et al ldquoEnhanced desensitiza-tion followed by unusual resensitization in GABAA receptorsin phospholipase C-related catalytically inactive protein-12double-knockout micerdquo Pflugers Archiv vol 467 no 2 pp 267ndash284 2014

[137] B Calabrese and S Halpain ldquoDifferential targeting of dynamin-1 and dynamin-3 to nerve terminals during chronic suppressionof neuronal activityrdquo Molecular and Cellular Neuroscience vol68 pp 36ndash45 2015

[138] D Suo J Park A W Harrington L S Zweifel S Mihalasand C D Deppmann ldquoCoronin-1 is a neurotrophin endosomaleffector that is required for developmental competition forsurvivalrdquo Nature Neuroscience vol 17 no 1 pp 36ndash45 2014

[139] J Lim H-S Choi and H J Choi ldquoEstrogen-related receptorgamma regulates dopaminergic neuronal phenotype by acti-vating GSK3120573NFAT signaling in SH-SY5Y cellsrdquo Journal ofNeurochemistry vol 133 no 4 pp 544ndash557 2015

[140] J R Cottrell B Li J W Kyung et al ldquoCalcineurin A120574 is afunctional phosphatase that modulates synaptic vesicle endo-cytosisrdquoThe Journal of Biological Chemistry vol 291 no 4 pp1948ndash1956 2016

[141] D C Hondius P van Nierop K W Li et al ldquoProfilingthe human hippocampal proteome at all pathologic stages ofAlzheimerrsquos diseaserdquo Alzheimerrsquos amp Dementia vol 12 no 6 pp654ndash668 2016

[142] G Pigino G Morfini Y Atagi et al ldquoDisruption of fast axonaltransport is a pathogenicmechanism for intraneuronal amyloidbetardquo Proceedings of the National Academy of Sciences of theUnited States of America vol 106 no 14 pp 5907ndash5912 2009

[143] E M Ramser K J Gan H Decker et al ldquoAmyloid-120573 oligomersinduce tau-independent disruption of BDNF axonal transportvia calcineurin activation in cultured hippocampal neuronsrdquoMolecular Biology of the Cell vol 24 no 16 pp 2494ndash2505 2013

[144] P Toglia K H Cheung D D Mak and G Ullah ldquoImpairedmitochondrial function due to familial Alzheimerrsquos disease-causing presenilinsmutants via Ca2+ disruptionsrdquoCell Calciumvol 59 no 5 pp 240ndash250 2016

[145] R Pigeat P Chausson F M Dreyfus N Leresche and R CLambert ldquoSleep slow wave-related homo and heterosynapticLTD of intrathalamic GABAAergic synapses involvement of T-type Ca2+ channels and metabotropic glutamate receptorsrdquoTheJournal of Neuroscience vol 35 no 1 pp 64ndash73 2015

[146] D M Raizen J E Zimmerman M H Maycock et alldquoLethargus is a Caenorhabditis elegans sleep-like staterdquo Naturevol 451 pp 569ndash572 2008

[147] C-O Wong K Chen Y Lin et al ldquoA TRPV channel indrosophila motor neurons regulates presynaptic resting Ca2+levels synapse growth and synaptic transmissionrdquoNeuron vol84 no 4 pp 764ndash777 2014

[148] M D Evans A S Dumitrescu D L H Kruijssen S E Taylorand M S Grubb ldquoRapid modulation of axon initial segmentlength influences repetitive spike firingrdquoCell Reports vol 13 no6 pp 1233ndash1245 2015

[149] K L Arendt Z Zhang S Ganesan et al ldquoCalcineurinmediateshomeostatic synaptic plasticity by regulating retinoic acidsynthesisrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 112 no 42 pp E5744ndashE5752 2015

[150] Y Hatanaka Y Hojo H Mukai et al ldquoRapid increase ofspines by dihydrotestosterone and testosterone in hippocampalneurons dependence on synaptic androgen receptor and kinasenetworksrdquo Brain Research vol 1621 pp 121ndash132 2015

[151] Y Hasegawa Y Hojo H Kojima et al ldquoEstradiol rapidly mod-ulates synaptic plasticity of hippocampal neurons involvementof kinase networksrdquo Brain Research vol 1621 pp 147ndash161 2015

[152] H Zhang J Liu S Sun E Pchitskaya E Popugaeva and IBezprozvanny ldquoCalcium signaling excitability and synapticplasticity defects in amousemodel of Alzheimerrsquos diseaserdquo Jour-nal of Alzheimerrsquos Disease vol 45 no 2 pp 561ndash580 2015

[153] A-H Chou Y-L Chen S-H Hu Y-M Chang and H-L Wang ldquoPolyglutamine-expanded ataxin-3impairslong-termdepression in Purkinje neurons of SCA3 transgenic mousebyinhibiting HAT andimpairing histone acetylationrdquo BrainResearch vol 1583 no 1 pp 220ndash229 2014

[154] J Zhang andM S Shapiro ldquoActivity-dependent transcriptionalregulation of M-Type (Kv7) K+ channels by AKAP79150-mediated NFAT actionsrdquo Neuron vol 76 no 6 pp 1133ndash11462012

[155] A D Williams S Jung and N P Poolos ldquoProtein kinase Cbidirectionally modulates 119868h and hyperpolarization-activatedcyclic nucleotide-gated (HCN) channel surface expression inhippocampal pyramidal neuronsrdquo Journal of Physiology vol593 no 13 pp 2779ndash2792 2015

[156] V Garcıa-Morales F Montero D Gonzalez-Forero et alldquoMembrane-derived phospholipids control synaptic neuro-transmission and plasticityrdquo PLoS Biology vol 13 no 5 ArticleID e1002153 2015

[157] S Kim and E B Ziff ldquoCalcineurinmediates synaptic scaling viasynaptic trafficking of Ca2+-permeable AMPA receptorsrdquo PLoSBiology vol 12 no 7 Article ID e1001900 2014

[158] T Yoshida and M Mishina ldquoDistinct roles of calcineurin-nuclear factor of activated T cells and protein kinase A-cAMPresponse element-binding protein signaling in presynaptic dif-ferentiationrdquo Journal of Neuroscience vol 25 no 12 pp 3067ndash3079 2005

[159] J G Murphy J L Sanderson J A Gorski et al ldquoAKAP-anchored PKA maintains neuronal L-type calcium channelactivity and NFAT transcriptional signalingrdquo Cell Reports vol7 no 5 pp 1577ndash1588 2014

[160] H LiMD Pink J GMurphy A SteinM LDellrsquoAcqua and PG Hogan ldquoBalanced interactions of calcineurin with AKAP79regulate Ca2+-calcineurin-NFAT signalingrdquo Nature Structuraland Molecular Biology vol 19 no 3 pp 337ndash345 2012

[161] S R Seo S S Kim and K C Chung ldquoActivation of adenylatecyclase by forskolin increases the protein stability of RCAN1(DSCR1 or Adapt78)rdquo FEBS Letters vol 583 no 19 pp 3140ndash3144 2009

[162] S Deheshi B Dabiri S Fan M Tsang and G L RintoulldquoChanges in mitochondrial morphology induced by calcium orrotenone in primary astrocytes occur predominantly throughros-mediated remodelingrdquo Journal of Neurochemistry vol 133no 5 pp 684ndash699 2015

[163] A M Slupe R A Merrill K H Flippo M A Lobas J C DHoutman and S Strack ldquoA calcineurin docking motif (LXVP)in dynamin-related protein 1 contributes to mitochondrial


fragmentation and ischemic neuronal injuryrdquo The Journal ofBiological Chemistry vol 288 no 17 pp 12353ndash12365 2013

[164] W-D C Krenz E W Rodgers and D J Baro ldquoTonic 5nM DAstabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated currentvia PKA and calcineurinrdquo PLoS ONE vol 10 no 2 Article IDe0117965 2015

[165] K Bacallao and P V Monje ldquoRequirement of cAMP signalingfor Schwann cell differentiation restricts the onset of myelina-tionrdquo PLoS ONE vol 10 no 2 Article ID e0116948 2015

[166] R Nagarajan J Svaren N Le T Araki M Watson and J Mil-brandt ldquoEGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expressionrdquo Neuron vol 30 no2 pp 355ndash368 2001

[167] K Bacallao and P V Monje ldquoOpposing roles of PKA andEPAC in the cAMP-dependent regulation of schwann cellproliferation and differentiationrdquo PLoS ONE vol 8 no 12Article ID e82354 2013

[168] M Finzsch S Schreiner T Kichko et al ldquoSox10 is required forSchwann cell identity and progression beyond the immatureSchwann cell stagerdquo Journal of Cell Biology vol 189 no 4 pp701ndash712 2010

[169] R I Peirano D E Goerich D Riethmacher and M WegnerldquoProtein zero gene expression is regulated by the glial transcrip-tion factor Sox10rdquoMolecular and Cellular Biology vol 20 no 9pp 3198ndash3209 2000

[170] A Rao ldquoSignaling to gene expression calcium calcineurin andNFATrdquo Nature Immunology vol 10 no 1 pp 3ndash5 2009

[171] S-W Jang and J Svaren ldquoInduction of myelin protein zeroby early growth response 2 through upstream and intragenicelementsrdquo The Journal of Biological Chemistry vol 284 no 30pp 20111ndash20120 2009

[172] H Fansa G Keilhoff T Horn S Altmann G Wolf andW Schneider ldquoStimulation of Schwann cell proliferation andaxonal regeneration by FK 506rdquo Restorative Neurology andNeuroscience vol 16 no 2 pp 77ndash86 2000

[173] M-S Guzman-Lenis C Vallejo X Navarro and C CasasldquoAnalysis of FK506-mediated protection in an organotypicmodel of spinal cord damage heat shock protein 70 levels aremodulated in microglial cellsrdquo Neuroscience vol 155 no 1 pp104ndash113 2008

[174] S Nottingham P Knapp and J Springer ldquoFk506 treatmentinhibits caspase-3 activation and promotes oligodendroglialsurvival following traumatic spinal cord injuryrdquo ExperimentalNeurology vol 177 no 1 pp 242ndash251 2002

[175] L Dietz F Frommer A-L Vogel et al ldquoNFAT1 deficit andNFAT2 deficit attenuate EAE via different mechanismsrdquo Euro-pean Journal of Immunology vol 45 no 5 pp 1377ndash1389 2015

[176] S Ghosh S B Koralov I Stevanovic et al ldquoHyperactivation ofnuclear factor of activated T cells 1 (NFAT1) in T cells attenuatesseverity ofmurine autoimmune encephalomyelitisrdquoProceedingsof the National Academy of Sciences of the United States ofAmerica vol 107 no 34 pp 15169ndash15174 2010

[177] H M Abdul J L Furman M A Sama D M Mathis andC M Norris ldquoNFATs and Alzheimerrsquos diseaserdquo Molecular andCellular Pharmacology vol 2 no 1 pp 7ndash14 2010

[178] C M Norris I Kadish E M Blalock et al ldquoCalcineurintriggers reactiveinflammatory processes in astrocytes and isupregulated in aging and Alzheimerrsquos modelsrdquo Journal ofNeuroscience vol 25 no 18 pp 4649ndash4658 2005

[179] M Berrocal I Corbacho M Vazquez-Hernandez J Avila MR Sepulveda and A M Mata ldquoInhibition of PMCA activity bytau as a function of aging andAlzheimerrsquos neuropathologyrdquoBio-chimica et Biophysica ActamdashMolecular Basis of Disease vol1852 no 7 pp 1465ndash1476 2015

[180] M Berrocal D Marcos M R Sepulveda M Perez J Avilaand A M Mata ldquoAltered Ca2+ dependence of synaptosomalplasma membrane Ca2+-ATPase in human brain affected byAlzheimerrsquos diseaserdquoTheFASEB Journal vol 23 no 6 pp 1826ndash1834 2009

[181] C Conejero-Goldberg J J Gomar T Bobes-Bascaran et alldquoAPOE2 enhances neuroprotection against Alzheimerrsquos diseasethrough multiple molecular mechanismsrdquo Molecular Psychia-try vol 19 no 11 pp 1243ndash1250 2014

[182] H Hayashi R B Campenot D E Vance and J E VanceldquoProtection of neurons from apoptosis by apolipoprotein E-containing lipoproteins does not require lipoprotein uptakeand involves activation of phospholipase C1205741 and inhibition ofcalcineurinrdquo The Journal of Biological Chemistry vol 284 no43 pp 29605ndash29613 2009

[183] M Shinohara T Kanekiyo L Yang et al ldquoAPOE2 eases cogni-tive decline during aging clinical and preclinical evaluationsrdquoAnnals of Neurology vol 79 no 5 pp 758ndash774 2016

[184] H-Y Wu E Hudry T Hashimoto et al ldquoDistinct dendriticspine and nuclear phases of calcineurin activation after expo-sure to amyloid-120573 revealed by a novel fluorescence resonanceenergy transfer assayrdquo Journal of Neuroscience vol 32 no 15pp 5298ndash5309 2012

[185] J R Casanova M Nishimura and J W Swann ldquoThe effects ofearly-life seizures on hippocampal dendrite development andlater-life learning and memoryrdquo Brain Research Bulletin vol103 pp 39ndash48 2014

[186] HM Abdul M A Sama J L Furman et al ldquoCognitive declinein Alzheimerrsquos disease is associated with selective changes incalcineurinNFAT signalingrdquo The Journal of Neuroscience vol29 no 41 pp 12957ndash12969 2009

[187] K Bromley-Brits and W Song ldquoThe role of TMP21 in traf-ficking and amyloid-120573 precursor protein (APP) processing inAlzheimerrsquos diseaserdquo Current Alzheimer Research vol 9 no 4pp 411ndash424 2012

[188] A A Grolla G Fakhfouri G Balzaretti et al ldquoA120573 leads to Ca2+signaling alterations and transcriptional changes in glial cellsrdquoNeurobiology of Aging vol 34 no 2 pp 511ndash522 2013

[189] D Lim A Iyer V Ronco et al ldquoAmyloid beta deregulatesastroglial mGluR5-mediated calcium signaling via calcineurinand Nf-kBrdquo Glia vol 61 no 7 pp 1134ndash1145 2013

[190] S Liu S Zhang K Bromley-Brits et al ldquoTranscriptional reg-ulation of TMP21 by NFATrdquoMolecular Neurodegeneration vol6 article 21 2011

[191] J Luo L Sun X Lin et al ldquoA calcineurin- andNFAT-dependentpathway is involved in 120572-synuclein-induced degeneration ofmidbrain dopaminergic neuronsrdquo Human Molecular Geneticsvol 23 no 24 pp 6567ndash6574 2014

[192] G Caraveo P K Auluck L Whitesell et al ldquoCalcineurin deter-mines toxic versus beneficial responses to 120572-synucleinrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 111 no 34 pp E3544ndashE3552 2014

[193] E C Miller P J Teravskis B W Dummer X Zhao R LHuganir and D Liao ldquoTau phosphorylation and tau mislocal-izationmediate soluble A120573 oligomer-induced AMPA glutamatereceptor signaling deficitsrdquo European Journal of Neurosciencevol 39 no 7 pp 1214ndash1224 2014


[194] S-H Ma Q-X Zhuang W-X Shen Y-P Peng and Y-H QiuldquoInterleukin-6 reduces NMDAR-mediated cytosolic Ca2+ over-load and neuronal death via JAKCaN signalingrdquo Cell Calciumvol 58 no 3 pp 286ndash295 2015

[195] K Watanabe K Uemura M Asada et al ldquoThe participation ofinsulin-like growth factor-binding protein 3 released by astro-cytes in the pathology of Alzheimerrsquos diseaserdquoMolecular Brainvol 8 article 82 2015

[196] G Dobrowolny C Giacinti L Pelosi et al ldquoMuscle expressionof a local Igf-1 isoform protectsmotor neurons in anALSmousemodelrdquo Journal of Cell Biology vol 168 no 2 pp 193ndash199 2005

[197] AM Fernandez S JimenezMMecha et al ldquoRegulation of thephosphatase calcineurin by insulin-like growth factor I unveilsa key role of astrocytes in Alzheimerrsquos pathologyrdquo MolecularPsychiatry vol 17 no 7 pp 705ndash718 2012

[198] S Pons and I Torres-Aleman ldquoInsulin-like growth factor-Istimulates dephosphorylation of I120581B through the serine phos-phatase calcineurin (protein phosphatase 2B)rdquo Journal of Bio-logical Chemistry vol 275 no 49 pp 38620ndash38625 2000

[199] T Takadera and T Ohyashiki ldquoCaspase-dependent apoptosisinduced by calcineurin inhibitors was prevented by glycogensynthase kinase-3 inhibitors in cultured rat cortical cellsrdquo BrainResearch vol 1133 no 1 pp 20ndash26 2007

[200] S A Alvarez A Blanco M Fresno and M A Munoz-Fernandez ldquoTNF-120572 contributes to caspase-3 independentapoptosis in neuroblastoma cells role of NFATrdquo PLoS ONE vol6 no 1 Article ID e16100 2011

[201] A Canellada E Cano L Sanchez-Ruiloba F Zafra and J MRedondo ldquoCalcium-dependent expression of TNF-120572 in neuralcells is mediated by the calcineurinNFAT pathwayrdquoMolecularand Cellular Neuroscience vol 31 no 4 pp 692ndash701 2006

[202] B Ma J Yu C Xie et al ldquoToll-like receptors promote mito-chondrial translocation of nuclear transcription factor nuclearfactor of activated T-cells in prolonged microglial activationrdquoThe Journal of Neuroscience vol 35 no 30 pp 10799ndash108142015

[203] A M Fernandez S Fernandez P Carrero M Garcia-Garciaand I Torres-Aleman ldquoCalcineurin in reactive astrocytes playsa key role in the interplay between proinflammatory and anti-inflammatory signalsrdquo The Journal of Neuroscience vol 27 no33 pp 8745ndash8756 2007

[204] B Kim H-K Jeong J-H Kim S Y Lee I Jou and E-HJoe ldquoUridine 51015840-diphosphate induces chemokine expressionin microglia and astrocytes through activation of the P2Y6receptorrdquo Journal of Immunology vol 186 no 6 pp 3701ndash37092011

[205] J L Furman D M Sama J C Gant et al ldquoTargetingastrocytes Ameliorates neurologic changes in a mouse model ofAlzheimerrsquos diseaserdquo Journal of Neuroscience vol 32 no 46 pp16129ndash16140 2012

[206] H-S Hong J-Y Hwang S-M Son Y-H Kim M Moonand M-J Inhee ldquoFK506 reduces amyloid plaque burden andinduces MMP-9 in A120573PPPS1 double transgenic micerdquo Journalof Alzheimerrsquos Disease vol 22 no 1 pp 97ndash105 2010

[207] E Hudry H-Y Wu M Arbel-Ornath et al ldquoInhibition of theNFAT pathway alleviates amyloid beta neurotoxicity in amousemodel of Alzheimerrsquos diseaserdquo Journal of Neuroscience vol 32no 9 pp 3176ndash3192 2012

[208] S Kim R F Titcombe H Zhang et al ldquoNetwork compensationof cyclic GMP-dependent protein kinase II knockout in the hip-pocampus by Ca2+-permeable AMPA receptorsrdquo Proceedings of

the National Academy of Sciences of the United States of Americavol 112 no 10 pp 3122ndash3127 2015

[209] M I K Hamad A Jack O Klatt et al ldquoType I TARPs promotedendritic growth of early postnatal neocortical pyramidal cellsin organotypic culturesrdquo Development vol 141 no 8 pp 1737ndash1748 2014

[210] M Itakura I Watanabe T Sugaya and M Takahashi ldquoDirectassociation of the unique C-terminal tail of transmembraneAMPA receptor regulatory protein 120574-8 with calcineurinrdquo FEBSJournal vol 281 no 5 pp 1366ndash1378 2014

[211] D M MacLean S S Ramaswamy M Du J R Howe and VJayaraman ldquoStargazin promotes closure of the AMPA receptorligand-binding domainrdquoThe Journal of General Physiology vol144 no 6 pp 503ndash512 2014

[212] O R Rana E Saygili C Meyer et al ldquoRegulation of nervegrowth factor in the heart the role of the calcineurin-NFATpathwayrdquo Journal of Molecular and Cellular Cardiology vol 46no 4 pp 568ndash578 2009

[213] E Saygili O R Rana C Gunzel et al ldquoRate and irregularity ofelectrical activation during atrial fibrillation affect myocardialNGF expression via different signalling routesrdquo Cellular Sig-nalling vol 24 no 1 pp 99ndash105 2012

[214] T Minami K Yano M Miura et al ldquoThe down syndromecritical region gene 1 short variant promoters direct vascularbed-specific gene expression during inflammation in micerdquoJournal of Clinical Investigation vol 119 no 8 pp 2257ndash22702009

[215] M Sobrado B G Ramirez F Neria et al ldquoRegulator ofcalcineurin 1 (Rcan1) has a protective role in brain ischemiareperfusion injuryrdquo Journal of Neuroinflammation vol 9 article48 2012

[216] R R Baggott A Alfranca D Lopez-Maderuelo et alldquoPlasma membrane calcium ATPase isoform 4 inhibits vascu-lar endothelial growth factor-mediated angiogenesis throughinteraction with calcineurinrdquo Arteriosclerosis Thrombosis andVascular Biology vol 34 no 10 pp 2310ndash2320 2014

[217] C-J Liu Y-C Cheng K-W Lee et al ldquoLipopolysaccha-ride induces cellular hypertrophy through calcineurinNFAT-3 signaling pathway in H9c2 myocardiac cellsrdquo Molecular andCellular Biochemistry vol 313 no 1-2 pp 167ndash178 2008

[218] S Porta S A Serra M Huch et al ldquoRCAN1 (DSCR1) increasesneuronal susceptibility to oxidative stress a potential patho-genic process in neurodegenerationrdquo Human Molecular Genet-ics vol 16 no 9 pp 1039ndash1050 2007

[219] X Sun Y Wu B Herculano and W Song ldquoRCAN1 over-expression exacerbates calcium overloading-induced neuronalapoptosisrdquo PLoS ONE vol 9 no 4 Article ID e95471 2014

[220] M Perluigi G Pupo A Tramutola et al ldquoNeuropathologi-cal role of PI3KAktmTOR axis in Down syndrome brainrdquoBiochimica et Biophysica ActamdashMolecular Basis of Disease vol1842 no 7 pp 1144ndash1153 2014

[221] S-Y Shin H W Yang J-R Kim W D Heo and K-H Cho ldquoAhidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling networkrdquo Journal of Cell Science vol 124 no 1pp 82ndash90 2011

[222] Y Wu P T T Ly andW Song ldquoAberrant expression of RCAN1in Alzheimerrsquos pathogenesis a new molecular mechanism anda novel drug targetrdquo Molecular Neurobiology vol 50 no 3 pp1085ndash1097 2014

[223] X Liogier drsquoArdhuy J O Edgin C Bouis et al ldquoAssessmentof cognitive scales to examine memory executive function and


language in individuals with down syndrome implications ofa 6-month observational studyrdquo Frontiers in Behavioral Neuro-science vol 9 article 300 2015

[224] F Stagni A Giacomini S Guidi E Ciani and R BartesaghildquoTiming of therapies for downsyndrome the sooner the betterrdquoFrontiers in Behavioral Neuroscience vol 9 article 265 2015

[225] E H Lee S S Kim S Lee K-H Baek and S R Seo ldquoPituitaryAdenylate Cyclase-Activating Polypeptide (PACAP) targetsdown syndrome candidate region 1 (DSCR1RCAN1) to controlneuronal differentiationrdquo The Journal of Biological Chemistryvol 290 no 34 pp 21019ndash21031 2015

[226] Y Li JWang Y ZhouD Li andZ-Q Xiong ldquoRcan1 deficiencyimpairs neuronal migration and causes periventricular hetero-topiardquo The Journal of Neuroscience vol 35 no 2 pp 610ndash6202015

[227] V Cavallucci E Bisicchia M T Cencioni et al ldquoAcute focalbrain damage alters mitochondrial dynamics and autophagyin axotomized neuronsrdquo Cell Death and Disease vol 5 articlee1545 2014

[228] B M Edens N Miller and Y Ma ldquoImpaired autophagy anddefective mitochondrial function converging paths on the roadto motor neuron degenerationrdquo Frontiers in Cellular Neuro-science vol 10 article 44 2016

[229] S Ghavami S Shojaei B Yeganeh et al ldquoAutophagy and apop-tosis dysfunction in neurodegenerative disordersrdquo Progress inNeurobiology vol 112 pp 24ndash49 2014

[230] V G Yerra and A Kumar ldquoAdenosine monophosphate-activated protein kinase abates hyperglycaemia-induced neu-ronal injury in experimental models of diabetic neuropathyeffects on mitochondrial biogenesis autophagy and neuroin-flammationrdquoMolecular Neurobiology 2016

[231] J Park D G Lee B Kim et al ldquoIron overload triggersmitochondrial fragmentation via calcineurin-sensitive signalsin HT-22 hippocampal neuron cellsrdquo Toxicology vol 337 pp39ndash46 2015

[232] J Mu Y Song J Zhang W Lin and H Dong ldquoCalcium sig-naling is implicated in the diffuse axonal injury of brain stemrdquoInternational Journal of Clinical and Experimental Pathologyvol 8 no 5 pp 4388ndash4397 2015

[233] B Gabryel A Pudelko J Adamczyk I Fischer and AMaleckildquoCalcineurin and Erk12-signaling pathways are involved in theantiapoptotic effect of cyclosporin A on astrocytes exposed tosimulated ischemia in vitrordquoNaunyn-Schmiedebergrsquos Archives ofPharmacology vol 374 no 2 pp 127ndash139 2006

[234] B Gabryel M Chalimoniuk A Stolecka K Waniek J Lang-fort and A Malecki ldquoInhibition of arachidonic acid releaseby cytosolic phospholipase A

2is involved in the antiapoptotic

effect of FK506 and cyclosporinA on astrocytes exposed to sim-ulated ischemia in vitrordquo Journal of Pharmacological Sciencesvol 102 no 1 pp 77ndash87 2006

[235] S Jayanthi X Deng B Ladenheim et al ldquoCalcineurinNFAT-induced up-regulation of the Fas ligandFas death pathway isinvolved in methamphetamine-induced neuronal apoptosisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 3 pp 868ndash873 2005

[236] Y Xu L Yang S Yu et al ldquoSpatiotemporal changes in NFATc4expression of retinal ganglion cells after light-induced damagerdquoJournal of Molecular Neuroscience vol 53 no 1 pp 69ndash77 2014

[237] C Ni Z Li M Qian Y Zhou J Wang and X Guo ldquoIsofluraneinduced cognitive impairment in aged rats through hippocam-pal calcineurinNFAT signalingrdquo Biochemical and BiophysicalResearch Communications vol 460 no 4 pp 889ndash895 2015

[238] Y Yang S Song H Min X Chen and Q Gao ldquoSTAT3 degra-dation mediated by calcineurin involved in the neurotoxicity ofisofluranerdquo NeuroReport vol 27 no 2 pp 124ndash130 2016

[239] F Neria M del Carmen Serrano-Perez P Velasco K UrsoP Tranque and E Cano ldquoNFATc3 promotes Ca2+-dependentMMP3 expression in astroglial cellsrdquo Glia vol 61 no 7 pp1052ndash1066 2013

[240] M A Sama D M Mathis J L Furman et al ldquoInterleukin-1120573-dependent signaling between astrocytes and neurons dependscritically on astrocytic calcineurinNFAT activityrdquo Journal ofBiological Chemistry vol 283 no 32 pp 21953ndash21964 2008

[241] K Szydlowska M Zawadzka and B Kaminska ldquoNeuroprotec-tant FK506 inhibits glutamate-induced apoptosis of astrocytesin vitro and in vivordquo Journal of Neurochemistry vol 99 no 3pp 965ndash975 2006

[242] NH Shah A J Schulien K Clemens et al ldquoCyclin E1 regulatesKv21 channel phosphorylation and localization in neuronalischemiardquo Journal of Neuroscience vol 34 no 12 pp 4326ndash43312014

[243] D J Gerber D Hall T Miyakawa et al ldquoEvidence for associa-tion of schizophrenia with genetic variation in the 8p213 genePPP3CC encoding the calcineurin gamma subunitrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 100 no 15 pp 8993ndash8998 2003

[244] T Miyakawa L M Leiter D J Gerber et al ldquoConditionalcalcineurin knockoutmice exhibitmultiple abnormal behaviorsrelated to schizophreniardquo Proceedings of the National Academyof Sciences of the United States of America vol 100 no 15 pp8987ndash8992 2003

[245] C A Ogden M E Rich N J Schork et al ldquoCandidate genespathways and mechanisms for bipolar (manic-depressive) andrelated disorders an expanded convergent functional genomicsapproachrdquo Molecular Psychiatry vol 9 no 11 pp 1007ndash10292004

[246] N Park S H Juo R Cheng et al ldquoLinkage analysis of psychosisin bipolar pedigrees suggests novel putative loci for bipolardisorder and shared susceptibility with schipzopreniardquo Mole-cular Psychiatry vol 9 no 12 pp 1091ndash1099 2004

[247] Y Tian I Voineagu S P Pasca et al ldquoAlteration in basal anddepolarization induced transcriptional network in iPSCderivedneurons fromTimothy syndromerdquoGenomeMedicine vol 6 no10 article 75 2014

[248] G QuadratoM Y Elnaggar C Duman A Sabino K Forsbergand S Di Giovanni ldquoModulation of GABAA receptor sig-naling increases neurogenesis and suppresses anxiety throughNFATc4rdquoThe Journal of Neuroscience vol 34 no 25 pp 8630ndash8645 2014

[249] C Crozatier S Farley I M Mansuy S Dumas B Giros and ET Tzavara ldquoCalcineurin (protein phosphatase 2B) is involvedin the mechanisms of action of antidepressantsrdquo Neurosciencevol 144 no 4 pp 1470ndash1476 2007

[250] S L Eastwood P W J Burnet and P J Harrison ldquoDecreasedhippocampal expression of the susceptibility gene PPP3CC andother calcineurin subunits in schizophreniardquo Biological Psychi-atry vol 57 no 7 pp 702ndash710 2005

[251] N Kozlovsky E Scarr B Dean and G Agam ldquoPostmortembrain calcineurin protein levels in schizophrenia patients arenot different from controlsrdquo Schizophrenia Research vol 83 no2-3 pp 173ndash177 2006

[252] H K Manji I I Gottesman and T D Gould ldquoSignal transduc-tion and genes-to-behaviors pathways in psychiatric diseasesrdquoSciencersquos STKE vol 2003 no 207 article pe49 2003


[253] W J Rushlow Y H Seah D J Belliveau and N RajakumarldquoChanges in calcineurin expression induced in the rat brainby the administration of antipsychoticsrdquo Journal of Neurochem-istry vol 94 no 3 pp 587ndash596 2005

[254] T D McClure-Begley S R Grady M J Marks A C Collinsand J A Stitzel ldquoPresynaptic GABAB autoreceptor regula-tion of nicotinic acetylcholine receptor mediated [3H]-GABArelease frommouse synaptosomesrdquo Biochemical Pharmacologyvol 91 no 1 pp 87ndash96 2014

[255] T-T Tzeng H-J Tsay L Chang et al ldquoCaspase 3 involves inneuroplasticity microglial activation and neurogenesis in themice hippocampus after intracerebral injection of kainic acidrdquoJournal of Biomedical Science vol 20 no 1 article 90 2013

[256] H Tokuoka T Hatanaka D Metzger and H Ichinose ldquoNurr1expression is regulated by voltage-dependent calcium channelsand calcineurin in cultured hippocampal neuronsrdquo Neuro-science Letters vol 559 pp 50ndash55 2014

[257] C Freire-Cobo G Sierra-Paredes M Freire and G Sierra-Marcuno ldquoThe calcineurin inhibitor Ascomicin interferes withthe early stage of the epileptogenic process induced by Latrun-culin A microperfusion in rat hippocampusrdquo Journal of Neu-roimmune Pharmacology vol 9 no 5 pp 654ndash667 2014

[258] G Sierra-Paredes and G Sierra-Marcuno ldquoAscomycin andFK506 pharmacology and therapeutic potential as anticonvul-sants and neuroprotectantsrdquo CNS Neuroscience and Therapeu-tics vol 14 no 1 pp 36ndash46 2008

[259] A Vazquez-Lopez G Sierra-Paredes and G Sierra-MarcunoldquoSeizures induced by microperfusion of glutamate and glycinein the hippocampus of rats pretreated with latrunculin ArdquoNeuroscience Letters vol 388 no 2 pp 81ndash85 2005

[260] M L Roberts-Crowley and A R Rittenhouse ldquoCharacteriza-tion of ST14A cells for studying modulation of voltage-gatedcalcium channelsrdquo PLoSONE vol 10 no 7 Article ID e01324692015

[261] I O Medvedev A J Ramsey S T Masoud et al ldquoD1 dopaminereceptor coupling to PLC120573 regulates forward locomotion inmicerdquo The Journal of Neuroscience vol 33 no 46 pp 18125ndash18133 2013

[262] L D Walensky and S H Snyder ldquoInositol 145-trisphosphatereceptors selectively localized to the acrosomes of mammalianspermrdquo Journal of Cell Biology vol 130 no 4 pp 857ndash869 1995

[263] G Ramazzotti A Bavelloni W Blalock M Piazzi L Coccoand I Faenza ldquoBMP-2 induced expression of PLC1205731 that is apositive regulator of osteoblast differentiationrdquo Journal of Cel-lular Physiology vol 231 no 3 pp 623ndash629 2016

[264] J Brotchie and P Jenner ldquoNew approaches to therapyrdquo Interna-tional Review of Neurobiology vol 98 pp 123ndash150 2011

[265] S N A Bukhari and I Jantan ldquoSynthetic curcumin analogsas inhibitors of 120573-amyloid peptide aggregation potential ther-apeutic and diagnostic agents for Alzheimerrsquos diseaserdquo Mini-Reviews in Medicinal Chemistry vol 15 no 13 pp 1110ndash11212015

[266] J Segura-Aguilar P Munoz and I Paris ldquoAminochrome as newpreclinical model to find new pharmacological treatment thatstop the development of Parkinsons diseaserdquo Current MedicinalChemistry vol 23 no 4 pp 346ndash359 2016

[267] L Brandenstein M Schweizer J Sedlacik J Fiehler and SStorch ldquoLysosomal dysfunction and impaired autophagy ina novel mouse model deficient for the lysosomal membraneproteinCln7rdquoHumanMolecular Genetics vol 25 no 4 pp 777ndash791 2016

[268] G Natale P Lenzi G Lazzeri et al ldquoCompartment-dependentmitochondrial alterations in experimental ALS the effectsof mitophagy and mitochondriogenesisrdquo Frontiers in CellularNeuroscience vol 9 article 434 2015

[269] DM Samy C A Ismail R A Nassra T M Zeitoun and AMNomair ldquoDownstream modulation of extrinsic apoptotic path-way in streptozotocin-induced Alzheimerrsquos dementia in ratserythropoietin versus curcuminrdquo European Journal of Pharma-cology vol 770 pp 52ndash60 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


activation is increasingly linked to pathological featuresof neurodegenerative diseases such as amyotrophic lateralsclerosis Huntingtonrsquos Parkinsonrsquos andAlzheimerrsquos diseasescharacterized by massive synaptic dysfunction glial activa-tion and neuronal death in some regions of the brain [26ndash29] CalcineurinNFAT involvement has also been reportedin psychiatric disorders epilepsy and traumatic brain andspinal cord injuries [30ndash35] Moreover recent data also sug-gest that NFAT isoforms are selectively activated in neuronsand glial cells in nervous system diseases [36 37] and animalmodels [38ndash41]

Herein we discuss the current understanding of the roleof calcineurinNFAT signaling pathway in both physiologyand pathologies of the adult and developing nervous systemwith an emphasis on recent reports and cutting-edge findings

2 CalcineurinNFAT Pathway

21 Calcineurin Calcineurin also termed as proteinphosphatase B (PP2B) is a Ca2+CaM-dependent serinethreonine phosphatase It was described for the first time inthe bovine brain about 40 years ago [42 43] Calcineurin ismade up of a 61 kD CaM-binding catalytic subunit termedcalcineurin A (CnA) and a 19 kD Ca2+-binding regulatorysubunit named calcineurin B (CnB) stably associated(noncovalently) [44 45] To date three isozymes of thecatalytic subunit (CnA120572 CnA120573 and CnA120574) have beenreported There are two isoforms of the regulatory subunitnamely CnB1 and CnB2 In vertebrates each subunit isencoded by a separate gene PPP3CA PPP3CB and PPP3CCfor CnB1 and PPP3R1 PPP3R2 for CnB2 [46 47] The twocalcineurin isoforms are widely distributed in mammaliantissues Immunohistochemical studies showed that undernormal conditions calcineurin isoforms are highly expressedin neuroinflammation-sensible neurons like corticohypo-thalamic pyramidal cells and cerebellar Purkinje cellsas well as in peripheral nervous system (PNS) glia likeSchwann cells but not in central nervous system (CNS) glia[37 48 49]

The subcellular distribution of calcineurin is an impor-tant control point in regulating its activity Various studiesaddressed the subcellular localization of calcineurin in var-ious mammalian cells [2 50 51] In neurons calcineurin wasfound in the cytoplasm endoplasmic reticulum Golgi appa-ratus nucleus synaptic vesicles microsomes mitochondrionouter membrane and plasma membrane [2 48 49 51 52]

22 NFAT Transcription Factors NFAT proteins are a familyof transcription factors normally found in the cytoplasm ina hyperphosphorylated (inactive) state [53ndash55] This familycomprises five distinct gene products termed (i) NFATcNFAT2 or NFATc1 (ii) NFATp NFAT1 or NFATc2 (iii)NFATx NFAT4 or NFATc3 (iii) NFAT3 or NFATc4 and(iv) osmotic response element-binding protein (OREBP)tonicity-responsive binding-protein (TonEBP) or NFAT5[56 57] In the context of this review nomenclature ofNFATc1-c4 and NFAT5 will be used

NFATc1ndashc4 occur as monomers with unique aminoand carboxyl termini containing transcription activation

domains (TADs) and two conserved domains (i) a regulatorydomain termedNFAThomology region (NHR) which showsa lesser degree of pair-wise sequence identity but has severalstrongly conserved sequence motifs characteristic of theNFAT family and (ii) the Rel homology region (RHR) inthe C-terminus where the DNA binding domain (DBD) islocated [14 56] The NHR encompasses calcineurin dockingsites a nuclear localization signal (NLS) responsible forcalcineurin-mediated nuclear translocation and an extendedserine-rich region [44 58ndash61] On the other hand the DBDbinds DNA and interacts with partner proteins to transac-tivate gene transcription Examples of partner transcriptionfactors include AP-1 cell life and death regulators [dimerictranscription factors composed of activating transcriptionfactor (ATF) Fos or Jun subunits] and important oncogenicregulators likemyocyte enhancer factor-2 (MEF2) andGATAbinding protein 4 (GATA4) [60 62] Regions out of the reg-ulatory and DNA binding domains like TADs demonstraterelatively little sequence conservation [57 59] NFAT5 is ahomodimer with a distinct domain structure This isoformretains only the RHR region of homology to the Ca2+-regulated isoforms whilst the remaining 600 amino acids arecompletely different The DBD of NFATs is distantly relatedto the DBD of nuclear factor kappa B (NF-120581B)Rel familyallowing them to be classified sometimes as members of thisextended family [63 64]

NFATs regulate the transcriptional induction of genesencoding for immune modulatorsactivators such as gran-ulocyte-macrophage colony-stimulating factor (GM-CSF)forkhead box P3 (FOXP3) immunoglobulin kappa (Ig120581)gamma interferon (IFN120574) CD5 CD25 CD28 CD40interleukin- (IL-) 2 IL-3 IL-4 IL-5 IL-13 IL-8 Th2-typecytokine IL-31 Fas ligand macrophage inflammatory protein1 alpha (MIP-1120572) protein tyrosine kinase Syk cyclooxygenase2 (COX-2) and tumor necrosis factor alpha (TNF-120572) and itsfamilymember BlyS NFATsmay also control genes encodingsignaling molecules as variate as Ca2+ regulators [inositol145-trisphosphate (IP

3) receptor (IP

3R) regulator of cal-

cineurin 1 (RCAN1)] growth factors (VEGF neurotrophins)myelination genes (P0 and Krox-20) glucose regulationgenes (insulin HNF1 PDX and GLUT2) cell cycle anddeath regulatoractivators [p21Waf1 c-Myc cyclin-dependentkinase 4 (CDK4) B-cell lymphoma 2 (Bcl-2) and cyclinsA2 D1 and D2] oncogenes (Wnt 120573-catenin) microRNAs(miR-21 miR-23 miR-24 miR-27 miR-125 miR-195 miR-199 and miR-224) and surfactants (sftpa sftpb sftpc andabca3) [9 65ndash74] NFAT isoforms are ubiquitously expressedand are generally regulated by Ca2+ signaling with exceptionof NFAT5 [59 75 76] NFAT5 regulates hypertonic stress-induced gene transcription whereas the other NFATs actas integrators of Ca2+ driven signaling pathways in geneexpression and cell differentiation programs [57 77 78]

All Ca2+-regulated NFATs (NFATc1ndashc4) are expressed inneurons [79]The previously assumed functional redundancyof NFAT functions was proved wrong by their wide-rangingexpression profile among cell types under both physiologicaland pathological conditions For example loss of specificNFAT subtypes resulted in cardiovascular skeletal muscle







3R1ndash






2- terminal kinases




























IP3R1-3

ERstores

RyR1-3


membrane


Cell membrane




Calcineurin

NFATc

PLCIP3








microglia



Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+Ca2+
























































Competing Interests


References





































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















3R1ndash






2- terminal kinases




























IP3R1-3

ERstores

RyR1-3


membrane


Cell membrane




Calcineurin

NFATc

PLCIP3








microglia



Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+Ca2+
























































Competing Interests


References





































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































IP3R1-3

ERstores

RyR1-3


membrane


Cell membrane




Calcineurin

NFATc

PLCIP3








microglia



Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+Ca2+
























































Competing Interests


References





































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































Competing Interests


References





































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the emerging roles of the calcineurin...

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