autocrine signaling involved in cell volume regulation: the role of released transmitters and plasma...

REVIEW ARTICLE 14J o u r n a l o fJ o u r n a l o f

CellularPhysiologyCellularPhysiology
Autocrine Signaling Involved in
Cell Volume Regulation: The Roleof Released Transmitters andPlasma Membrane Receptors
RODRIGO FRANCO,1,2* MIHALIS I. PANAYIOTIDIS,3 AND LENIN D. OCHOA DE LA PAZ4
1Laboratory of Cell Biology and Signal Transduction, Biomedical Research Unit, FES-Iztacala, UNAM, Mexico2Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health,

Research Triangle Park, North Carolina3School of Public Health, University of Nevada. Reno, Nevada4School of Biological Science, Department of Neurobiology and Behavior, University of California-Irvine, Irvine, California

Cell volume regulation is a basic homeostatic mechanism transcendental for the normal physiology and function of cells. It is mediatedprincipally by the activation of osmolyte transport pathways that result in net changes in solute concentration that counteract cell volumechallenges in its constancy. This process has been described to be regulated by a complex assortment of intracellular signal transductioncascades. Recently, several studies have demonstrated that alterations in cell volume induce the release of a wide variety of transmittersincluding hormones, ATP and neurotransmitters, which have been proposed to act as extracellular signals that regulate the activation ofcell volume regulatory mechanisms. In addition, changes in cell volume have also been reported to activate plasma membrane receptors(including tyrosine kinase receptors, G-protein coupled receptors and integrins) that have been demonstrated to participate in theregulatory process of cell volume. In this review, we summarize recent studies about the role of changes in cell volume in the regulation oftransmitter release as well as in the activation of plasma membrane receptors and their further implications in the regulation of thesignalingmachinery that regulates the activation of osmolyte flux pathways.We propose that the autocrine regulation of Ca2þ-dependentand tyrosine phosphorylation-dependent signaling pathways by the activation of plasma membrane receptors and swelling-inducedtransmitter release is necessary for the activation/regulation of osmolyte efflux pathways and cell volume recovery. Furthermore, weemphasize the importance of studying these extrinsic signals because of their significance in the understanding of the physiology of cellvolume regulation and its role in cell biology in vivo, where the constraint of the extracellular space might enhance the autocrine or evenparacrine signaling induced by these released transmitters.J. Cell. Physiol. 216: 14–28, 2008. � 2008 Wiley-Liss, Inc.

Abbreviations: RVD, regulatory volume decrease; RVI, regulatoryvolume increase; TKR, tyrosine kinase receptor; GPCR, G-proteincoupled receptor; FAK, focal adhesion kinase; EGF, epidermalgrowth factor; EGFR, epidermal growth factor receptor; ABC-T,ATP binding cassette transporter; ATP, adenosine triphosphate;PI3K, phosphatidyl inositide-3 kinase; P2Y, metabotropicpurinoreceptor; P2X, ionotropic purinoreceptor; PKC, proteinkinase C; PKA, protein kinase A; PLC, phospholipase C; VSOAC,volume sensitive osmolyte/anion channel; VRAC, volume regulatedanion channel; EAA, excitatory amino acids.

Contract grant sponsor: Intramural Research Program of the NIH/National Institute of Environmental Health Sciences.Contract grant sponsor: UCMEXUS-CONACYT PostdoctoralFellowship Program.

*Correspondence to: Rodrigo Franco, Laboratory of Cell Biologyand Signal Transduction, Biomedical Research Unit, FES-Iztacala,UNAM, Av. de los Barrios 1, Los Reyes Iztacala, Tlalnepantla, Edo.de Mexico, C.P. 54090, Mexico.E-mail: [email protected]

Received 23 October 2007; Accepted 3 January 2008

DOI: 10.1002/jcp.21406

The volume of a cell can be defined as its dimensions which arerelated to its form, size and environment. Cell volume is mainlydetermined by a strict balance between both the intracellularand extracellular concentration of osmolytes. Thus, cell volumehomeostasis is a process accomplished by the net osmolytetranslocation through the plasma membrane in the necessarydirection to counteract changes in cell volume due to net watermovements. Because themaintenance of a constant cell volumeis a challenge faced by all cell types, the regulation of cell volumeconstancy is a basic and transcendental homeostaticmechanismconserved throughout evolution (Macknight et al., 1994;Strange, 2004).

In physiological conditions, cell volume is continuouslycompromised by the presence of impermeant and negativelycharged molecules such as nucleic acids and proteins, andthe additional osmotic force generated by the asymmetricaldistribution of permeant ions (Gibbs–Donnan equilibrium),as well as by changes in the osmotic equilibrium between theextracellular and the intracellular space (Chamberlin andStrange, 1989; Parker, 1993;Wehner et al., 2003). For example,changes in the concentration of intracellular osmolytes occur inassociation with processes such as secretion, accumulation ofnutrients, ion gradients, neurotransmitter transport, synthesisand breakdown of macromolecules, cell migration, cell growth,migration and proliferation, and apoptosis (Dubois andRouzaire-Dubois, 2004; Umen, 2005; Jakab and Ritter, 2006;McFerrin and Sontheimer, 2006; Mulligan and MacVicar, 2006;Stutzin and Hoffmann, 2006; Lang, 2007; Lang et al., 2007).Additionally, disturbances in normal cell volume challenge cellhomeostasis due to its participation as a messenger for

� 2 0 0 8 W I L E Y - L I S S , I N C .

metabolic control, as a signal for growth and proliferation, andas a trigger for mechanisms initiating insertion of membraneproteins, channels, receptors and transporters (Waldeggeret al., 1998; O’Neill, 1999; Cooper, 2004; Schreiber, 2005;

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Meyers et al., 2006). Deregulation of cell volume homeostasis,on the other hand, has been related to differentpathophysiological conditions including, but not only, cerebraledema, hypercatabolic states, diabetes mellitus, chronic renalfailure, sickle cell disease and uraemia (Strange, 1992; McManuset al., 1995;Waldegger et al., 1998;Won et al., 2002; Pasantes-Morales et al., 2002b; Haussinger, 2004; Bringmann et al., 2005;Kimelberg, 2005; Kocic, 2005; Leis et al., 2005;Norenberg et al.,2005, 2007; Sterns and Silver, 2006; Verbalis, 2006; Liang et al.,2007; Mongin, 2007; Rosenblum, 2007).

The regulatory volume response of a cell to an osmoticchallenge can be dissected in three stages: first, the detection ofchanges in cell volume by a volume sensor; second, thetransduction of this signal through the activation of signaltransduction cascades; and third, the regulation and/oractivation of osmolyte transport pathways. A large amountof effort has been devoted to the characterization of themolecular processes involved in these three regulatorystages (Hoffmann and Pedersen, 1998; Jakab et al., 2002;Pasantes-Morales and Franco, 2002; Wehner et al., 2003;Hoffmann and Pedersen, 2006; Alexander and Grinstein,2006a). Results so far have underscored the wide diversity ofprocesses involved in cell volume regulation that have led to thenotion of a complex system involved in this phenomenon. Thislevel of complexity has been increased by recent observationsshowing that alterations in cell volume induce the release ofhormones and transmitters that might modulate the regulatoryvolume response by autocrine or paracrine signal transductionloops (Strbak and Greer, 2000; Pasantes-Morales et al., 2002a;Najvirtova et al., 2003; Strbak, 2006). In addition, changes in cellvolume have also been reported to regulate the activation ofplasmamembrane receptors (Franco et al., 2004a; Lezama et al.,2005a). Throughout this review article, we discuss evidencesuggesting that cell volume changes are important modulatorsof hormone and transmitter release as well as plasmamembrane receptor activation, and that these events areimportant in the signaling processes involved in cell volumeregulation and in normal cell function. This hypothesis acquiresmore relevance when we consider the restriction of theextracellular space in integrated systems including tissues,organs and in vivo systems. Finally, we propose that therelease of these messengers, and the activation of plasmamembrane receptors during cell swelling, regulatean interdependent Ca2þ-dependent and tyrosinekinase-dependent signaling cascade that is involved in theregulation and activation of osmolyte efflux pathways.

Cell Volume Regulatory Mechanisms

Alterations in cell volume constancy are compensated bythe regulation of intracellular osmolyte content either bymodulating membrane transport or metabolic pathways.In general, cell volume regulation can be classified as eithersteady-state or acute regulatory processes. Steady-stateregulation of cell volume occurs in the presence of a constantisosmotic environment. In this situation cells maintain aconstancy in their cell volume by two mechanisms: (1) theactivity of theNaþ–Kþ–ATPase, whose ability to create a lowerion concentration environment by the extrusion Naþ inexchange of Kþ compensates the osmolarity imposed by thepresence of a large concentration of impermeant molecules;and (2) the selective permeability of the plasma membraneto Kþ but not Naþ, which results in an outward Kþ currentmediated by background Kþ channels coupled to the exit andextracellular accumulation of Cl� that counterbalances theassymetrical equilibrium of impermeant organic anions.Exceptions have been found in erythrocytes which lackNaþ–Kþ–ATPase, but net cation efflux is driven byCa2þ pumps

JOURNAL OF CELLULAR PHYSIOLOGY

and Naþ/Ca2þ exchangers (Hernandez and Cristina, 1998;Waldegger et al., 1998; O’Neill, 1999; Armstrong, 2003; Lang,2007).

Acute regulation of cell volume occurs in response tochanges in extracellular osmolarity or through alterations of theintracellular concentration of osmotically active molecules(osmolytes) (see Fig. 1). Acute cell volume regulation is basicallyaccomplished by two mechanisms: (1) the net loss ofintracellular osmolytes in response to cell swelling (a processcalled regulatory volume decrease or RVD); or (2) the netaccumulation of active solutes in response to cell shrinkage(regulatory volume increase or RVI). Numerous studies havebeen made towards the characterization and identificationof the osmolyte transport mechanisms and their molecularidentities. Readers are encouraged to consult recent reviewson this subject (Waldegger et al., 1998; O’Neill, 1999; Furstet al., 2002; Pasantes-Morales et al., 2002b, 2006b; Wehneret al., 2003; Lambert, 2004; Pasantes-Morales and Franco, 2004;Lang, 2007).

Regulatory volume decrease (or RVD) is accomplishedprimarily by the activation of specific transport systems thatextrude Kþ and Cl� (the two major intracellular inorganicosmolytes) together with organic osmolytes including aminoacids, polyols and methylamines. The transport pathwaysinvolved in Kþ loss have been identified in many cell types, andinvolve the activation of distinct Kþ channels whose molecularidentity seems to vary according to the cell type studied(Hoffmann and Hougaard, 2001; Wehner et al., 2003;Wehner,2006; Calloe et al., 2007; L’Hoste et al., 2007; Lotshaw, 2007).On the other hand, the molecular identity(ies) of the effluxpathways that mediate Cl� and organic osmolyte releaseremain elusive, although many candidates have been proposed(Nilius and Droogmans, 2003; Sardini et al., 2003; d’Anglemontde Tassigny et al., 2003; Okada, 2006; Suzuki et al., 2006). Thepharmacological and biophysical characterizationof these effluxpathways, however, has lead to the notion of a commonmechanism for both Cl� and organic osmolytes efflux namedvolume sensitive osmolyte/anion channel (VSOAC), or volumeregulated anion channel (VRAC). Nevertheless, recentevidence suggests that the osmolyte transporters involvedinCl� and organic anion releasemight also diverge according toosmolyte species involved (Davis-Amaral et al., 1996; Shennanand Thomson, 2000; Stegen et al., 2000; Franco et al., 2001;Franco, 2003; Tomassen et al., 2004a).Other transport systemsless commonly involved in RVD are the Kþ–Cl� cotransporter,and the Kþ/Hþ and Cl�/HCO3� exchangers (Waldegger et al.,1998; Wehner et al., 2003; Gamba, 2005; Adragna et al., 2006).On the other hand regulatory volume increase (or RVI), isachieved principally by the influx of Naþ (the main extracellularinorganic osmolyte) through the activation of specifictransporters including the Naþ/Hþ exchanger, theNaþ–Kþ–2Cl�-cotransporter and cation channels.Additionally, the activation of net organic osmolyte uptakesystems coupled to the Naþ gradient has been shown to beinvolved in RVI (Waldegger et al., 1998; Haas and Forbush,2000; Wehner et al., 2003; Orlowski and Grinstein, 2004;Franchi-Gazzola et al., 2006; Pedersen et al., 2006; Alexanderand Grinstein, 2006b; Hoffmann et al., 2007).

Studies of the processes involved in acute cell volumeregulation have been performed mainly in response to suddenchanges in osmolarity which might not reflect in vivo situationsthat occur during pathological osmotic disturbances. A newexperimental paradigm of gradual and small changes inosmolarity, first developed by Lohr and Granham (Lohr andGrantham, 1986; Lohr and Yohe, 2000) and then studied byothers (Mountian and Van Driessche, 1997; Franco et al., 2000;Pasantes-Morales and Franco, 2004; Ordaz et al., 2004a,b), hasdemonstrated the ability of the cells to maintain a constantvolume by the persistent modulation of the intracellular

Fig. 1. Cell volumeregulation. In isosmoticconditionstheextracellular[X]eand intracellular[X]i concentrationsofosmoticactivemoleculesorosmolytes is in equilibrium. Acute cell volume regulation is basically accomplished by two mechanisms: (1) regulatory volume decrease (RVD)mediatedby thenet lossof intracellularosmolytes in response tocell swelling inducedbyahyposmotic environment (a reduced [X]e compared tothe [X]i); and (2) regulatory volume increase (RVI) mediated by the net accumulation of active solutes in response to cell shrinkage induced bya hyperosmotic environment (an increased [X]e compared to the [X]i). These phenomena allow the cells to partially recover their originaldimensions and in thisway, prevent thedeleterious effects of changes in cell volume. Regulatory volumedecrease is accomplishedbasically by theactivationof specifictransport systemsthatextrudeKRandCl�, thetwomajor intracellular inorganicosmolytes, togetherwithorganicosmolytesincluding amino acids, polyols and methylamines. The transport pathways principally involve the activation of distinct ionic channels. Othertransport systems less commonly involved inRVDare theKR–Cl� cotransporter, theKR/HRand theCl�/HCO3�exchangers. RegulatoryVolumeIncrease on the other hand, is achieved principally by the influx of sodium (themain extracellular inorganic osmolyte) through the activation ofspecific transporters including the NaR/HR exchanger, the NaR–KR–2Cl�-cotransporter and cation channels. Additionally, the activation of netorganicosmolytesuptakesystemscoupledtotheNaRgradienthasbeenshowntobeinvolvedinRVI(Francoetal.,2000;Furstetal.,2002;NiliusandDroogmans, 2003;Wehner et al., 2003; Okada, 2006; Pedersen et al., 2006;Wehner, 2006; Pasantes-Morales et al., 2006b; Hoffmann et al., 2007;Lang, 2007).

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osmolyte contentwhich avoids changes in cell volume. This newparadigm might shed new light on the mechanisms involved inacute situations in vivo.

Signaling Cascades Involved in the Modulation ofOsmolyte Transport

The study of the transduction signals involved in the regulationof osmolyte transport has been recently undertaken. So far, avariety of signaling cascades have been described and proposed.In this way, an ample array of signaling mechanisms has beenreported to be activated in response to changes in cell volume,which suggests a complex sensory system thatmight involve theparallel activation of interdependent signaling cascades withmarked variations according to the osmolyte efflux pathwayand the cell type studied. Signal transduction research in cellvolume regulation can be divided into two groups: (1) studiesdealing with the characterization of the signaling cascades


involved in the regulation of osmolyte flux pathways; and(2) studies with the aim of identifying the nature of the cellvolume sensor. These subjects have been recently reviewedthoroughly (Eggermont et al., 2001; Jakab et al., 2002;Pasantes-Morales and Franco, 2002; Wehner et al., 2003;Okada, 2004; Hoffmann and Pedersen, 2006; Alexander andGrinstein, 2006a). In general, alterations in cell volume as astress condition activate a large group of signaling molecules.From these, it is important to distinguish between the onesactivated just as a response to the stress generated (bystandersignals), and those involved in the volume regulatory process.Another distinctionmust be drawn between the signals directlyinvolved in the activation of the osmolyte transport systems,and the ones involved in the modulation of its effectiveness.Indeed, recent reports have shown the effects of releasedtransmitters and the activation plasma membrane receptorsregulating either the activation or the efficiency of theregulatory volume process. We next summarize and discuss


evidence on how released transmitters, as a consequence ofchanges in cell volume, act as important signals involved in theregulation of osmolyte transport during cell volume.

Release of Transmitters Associated WithChanges in Cell Volume

Cell communication depends heavily on extracellular signalmolecules (transmitters), which are produced intracellularlyand when released, signal into feedback loops in the sameindividual cell (autocrine), or in other cells (paracrine). Thesetransmitters include hormones, ATP, and neurotransmittersincluding excitatory or inhibitory amino acids (GABA, glycine,glutamate), acetylcholine and monoamines. Changes in cellvolume have been widely reported to modulate the release oftransmitters (Pasantes-Morales et al., 1999, 2002a; Strbak andGreer, 2000; Jakab et al., 2002; Najvirtova et al., 2003; Strbak,2006). This has recently raisedmany questions about the role ofthese molecules in the activation/modulation of cell volumeregulatory processes.

Swelling-induced transmitter release

Cell swelling or stretch has been shown to induce the release ofdifferent types of transmitters including neurotransmitters,ATP and hormones (Sadoshima and Izumo, 1997; Apodaca,2002) (see Fig. 2). This phenomenon is not only restricted toexcitable cells but also to other types including cells of epithelialorigin. While most of the evidence so far suggests anexocytosis-dependent mechanism for transmitter release inresponse to changes in cell volume, othermechanisms includingchannel- and transporter-mediated transmitter extrusion havebeen reported. Hyposmotic swelling stimulates exocytosis in

Fig. 2. Mechanismsinvolvedinswelling-inducedtransmitterrelease.Cell swelling or stretch has been reported to induce the release of awide variety of transmitters including ATP, monoamines, hormones(suchas insulin) andexcitatory/inhibitoryaminoacids.Threedifferentmechanisms have been proposed for swelling-induced transmitterrelease, which include: (1) ion/osmolyte channels; (2) ATP-bindingcassette transporters such as CFTR and MRP-1; and(3) Ca2R-dependent or -independent exocytosis. Activation of thesetransmitter release pathways by cell swelling might be mediated bya direct tension-mediated process or by the activation of signaltransduction pathways including tyrosine kinases, phophatidylinositide kinases (PI3K), small G-proteins (Rho), changes in thestructure/dynamics of action cytoskeleton, or Ca2R rise throughintracellular pools or via activation of non-selective or Ca2R selectivechannels.


both aCa2þ-dependent andCa2þ-independentmanner (Okadaet al., 1992; Herring et al., 1998; Reid and O’Neil, 2000;Fedorovich et al., 2005; Takii et al., 2006). Although themechanisms associated with Ca2þ-dependent exocytosis arewell known (Sudhof, 2004), those of Ca2þ-independent vesiclefusion are still largely unclear. Several signaling processestransduce cell stretch to exocytosis including changes incytoskeleton, activation of integrins, phospholipases, tyrosinekinases and cAMP (Hamill and Martinac, 2001; Apodaca, 2002;Grinnell et al., 2003). Swelling-induced exocytosis possesseslimited selectivity. Cell swelling by hyposmolarity mediates thesecretion of distinct hormones. For example, renin secretioninduced by hypotonicity from renal juxtaglomerular cells hasbeen reported to be mediated by exocytosis (Friis et al., 1999).Exocytosis has also been shown to be the main mechanism fortransmitter excretion of thyrotropin releasing hormone(TRH), prolactin and insulin from the heart slices, pancreaticislets and various brain structures. Hyposmotic stimulation ofinsulin secretion is independent from both extracellular andintracellular Ca2þ (Strbak and Greer, 2000; Kinard et al., 2001;Najvirtova et al., 2003; Bacova et al., 2006; Beauwenset al., 2006; Strbak, 2006). Similarly, hyposmotic-inducedbeta-endorphin secretion from melanotropes has also beendemonstrated to be Ca2þ-independent. On the other hand,swelling-induced catecholamine exocytosis depends on theactivation of voltage gated Ca2þ-currents (Moser et al., 1995;Amatore et al., 2007). Interestingly, two distinct mechanisms(Ca2þ-dependent and -independent) have been described forinsulin secretion after hyposmotic shock in betaHC9 cells(Straub et al., 2002). Thus, Ca2þ-dependent and -independentmechanisms both seem to mediate vesicle fusion or exocytosisduring cell swelling.

The mechanisms involved in hyposmotic-inducedneurotransmitter release from central nervous systempreparations have also been studied (Pasantes-Morales et al.,2002a). Initial studies in cultured astrocytes suggested thathyposmotic-induced excitatory amino acid release (EAA)such as glutamate was being mediated through the activationof the VRAC studied by both electrophysiological andpharmacological approaches (Kimelberg et al., 1990; Roy, 1995;Rutledge et al., 1998). A reduction in the uptake mechanismsfor amino acids has also been reported to participate in thisphenomenon although its contribution was observed to beminimal (Kimelberg et al., 1995). In rat cortical synaptosomeshyposmotic-induced glutamate and GABA release is mediatedby the contribution of three distinct mechanisms includingexocytosis, VRAC-mediated efflux and reversal uptake (Tuzet al., 2004), while that of norepinephrine was demonstrated tobe a Ca2þ-dependent exocytosis modulated by protein kinase C(PKC) activation and inhibited by tetanus toxin (Tuz andPasantes-Morales, 2005). In rat hippocampal and brain cortexslices, glutamate and GABA release after cell swelling ismediated by a completely distinct pathway from that of VRAC.This pathway was shown to be insensitive to Cl� channelblockers and tyrosine kinase inhibitors. Moreover, this releasewas observed to be Ca2þ-independent and was potentiated bythe activation of PKC and cytoskeleton disruption (Francoet al., 2001; Pasantes-Morales et al., 2002a; Franco, 2003).Although in these studies D-aspartate was used as a tracer forglutamate, recent reports demonstrate that aspartate can bereleased by exocytosis (Savage et al., 2001; Wang and Nadler,2007). In addition, exocytosis of neurotransmitter amino acidshas been widely reported to be potentiated by PKC activators(such as PMA) and cytoskeleton depolymerization (Vaughanet al., 1998; Doussau and Augustine, 2000; Bouron, 2001;Iannazzo, 2001; Eitzen, 2003). These results suggest then apossible role of Ca2þ-independent exocytosis in amino acidrelease after cell swelling (Franco et al., 2001; Pasantes-Moraleset al., 2002a; Franco, 2003). Indeed, it has been proposed that


during cell swelling, Ca2þ-independent exocytosis ofneurotransmitter amino acids such as GABA and glutamateoccurs in a ‘‘kiss and run’’ mode (partial fusion), whileCa2þ-dependent exocytosis is mediated by full vesicle fusion(Fedorovich et al., 2005;Waseem et al., 2005). Finally, althoughit was suggested that astrocytes posses the necessarymachinery for vesicle exocytosis (Jeftinija et al., 1997; Evankoet al., 2004; Parpura et al., 2004; Malarkey and Parpura, 2008),it has been recently reported that release of glutamate fromastrocytes upon ischemic and osmotic stress conditions is dueto the activation of both maxi-anion channels and VSOAC(Pangrsic et al., 2006; Liu et al., 2006a). Similarly, D-aspartaterelease from PC12 cells upon hyposmotic stimuli seems to bemediated by VSOAC. Other transmitters are also released tothe extracellular medium under hypotonic-induced swellingconditions. Non-exocytotic release of acetylcholineby hypotonic Krebs was reported in different preparations(Hanna-Mitchell et al., 2007). Histamine, leukotrienes andprostaglandin E2 release have also been reported to be releasedby hyposmolarity (Lambert et al., 1987; Sernka, 1989; Liu et al.,2006a).

Swelling-induced adenosine triphosphate (ATP) release hasbeen widely reported in different cell types (Wang et al., 1996;Roman et al., 1999a,b; Sabirov et al., 2001; Shinozuka et al.,2001; Boudreault and Grygorczyk, 2002; Hisadome et al., 2002;Jans et al., 2002; Darby et al., 2003; van der Wijk et al., 2003;Evanko et al., 2004; Gatof et al., 2004; Ito et al., 2004; Ollivieret al., 2006), as well as in in vivo studies in rat cerebral cortex(Phillis andO’Regan, 2002; Phillis, 2004).However, controversystill exists about the mechanism of its release, which has beenreported mediated by either exocytosis (Boudreault andGrygorczyk, 2002; van derWijk et al., 2003;Gatof et al., 2004), atransporter (Roman et al., 1997; Braunstein et al., 2001, 2004;Darby et al., 2003; Reigada and Mitchell, 2005), or a channel(Wang et al., 1996; Roman et al., 1999a; Sabirov et al., 2001;Hisadome et al., 2002; Ito et al., 2004; Okada et al., 2004;Sabirov and Okada, 2004). This might be explained by multiplerelease mechanisms involved in swelling-induced ATP release.Indeed, a recent report suggests that hypotonic-induced ATPextrusion is mediated by a biphasic release by both exocytosisand ATP-conductive channels (Takemura et al., 2003). ATPrelease from different cell types has been suggested to bemediated and/or regulated by ABCC transporters including thecystic fibrosis transmembrane conductance regulator (CFTR),the multidrug resistance proteins (MRP) (Braunstein et al.,2001, 2004; Reigada and Mitchell, 2005) and the P-glycoprotein(Roman et al., 1997, 2001). Swelling-induced ATP releasefrom cultured astrocytes appears to be mediated by aCa2þ-independent MRP transport (Darby et al., 2003; Josephet al., 2003). In contrast swelling-induced ATP release fromepithelial cells and fibroblasts has been shown to be mediatedby Ca2þ-dependent exocytosis (Boudreault and Grygorczyk,2002, 2004) which is self-regulated autocrinally (Tatur et al.,2007). Release of ATP after cell swelling is regulated by distinctsignaling cascades. For example, swelling-induced exocytosisof ATP was demonstrated to be dependent on Ca2þ andcytoskeleton aswell as on the activation ofMAPK (ERK1/ERK2)and phospholipaseD in intestinal cells (van derWijk et al., 2003;Tomassen et al., 2004b), while activation of PI3K and PKC seemto regulate swelling-induced exocytosis of ATP in humancholangiocarcinoma cell lines and HTC hepatoma cells(Feranchak et al., 1998; Gatof et al., 2004). On the other hand,hyposmotic-induced ATP release from an aortic endothelialcell-line depends on tyrosine kinase and Rho-kinase signalingpathways (Koyama et al., 2001), while in Caco-2 cells, ATPrelease is regulated by caveolin-1 (Ullrich et al., 2006). Thesedata suggest that cell swelling is an important activator oftransmitter release and that the mechanisms involved seemto vary according to the cell type studied.


Shrinkage-induced transmitter release

Although in general it is thought that cell swelling evokes andshrinking inhibits exocytosis of transmitters from various typesof cells, someexceptions are found. For example, hyperosmoticstimulation induces the release of intranuclear oxytocin inthe paraventricular nucleus and the supraoptic nucleus whichis inhibited by GdCl3 (Strbak, 2006). Renin secretion byexocytosis has also been reported to be stimulated byhyperosmotic-shrinkage in kidney preparations (Kurtz andSchweda, 2006). In the next section we will focus on howtransmitter release after cell swelling regulates RVD andosmolyte flux pathways.

Autocrine Regulation of Cell Volume

Released transmitters after cell swelling (or their exogenousaddition) have been reported to modulate cell volumeregulatory pathways by the activation of specific signalingcascades. In general, we can group these signaling events bythe type of receptor being activated. Transmitters such asacetylcholine, glutamate, and ATP, act on either metabotropicreceptors or ionotropic receptors that primarilymediateCa2þ-dependent signaling.On the other hand, releasedhormones such as insulin are well known to activate tyrosinekinase receptor (TKR) signaling.

Activation of metabotropic receptors: The role ofcalcium signaling and serine-threonine kinases

Activation of metabotropic receptors or G-protein coupledreceptors (GPCR) such as those for ATP (P2Y) andacetylcholine (muscarinic) trigger a well known chain ofsignaling elements, leading to the activation PLC, IP3 formationand Ca2þ elevation (Lazarowski et al., 2003; Schwiebert andZsembery, 2003; Erb et al., 2006; Dorsam and Gutkind, 2007).On the other hand, activation of ionotropic receptors such asthose of ATP (P2X) and excitatory amino acids EAA (NMDA)mediate non-selective cation conductances that allow the influxof both Naþ and Ca2þ from the extracellular space. In thisway, Ca2þ-dependent signaling seems to be the most plausiblecandidate for the effect of released transmitter on cell volumeregulatory processes. Hyposmolarity induces Ca2þ release in alarge variety of cell lines (McCarty and O’Neil, 1992; Pasantes-Morales and Morales-Mulia, 2000). In these conditions, thesource of Ca2þ has been reported to involve both extracellularand intracellular pools. Activation of transient receptorpotential (TRP) channels which mediate Ca2þ-influx from theextracellular space, has been recently reported to regulateRVD (Jorgensen et al., 1996; Ramakrishnan et al., 1998; Grimmet al., 2003; Xu et al., 2003; Jia et al., 2004; Vriens et al., 2004;Becker et al., 2005; O’Neil and Heller, 2005; Liu et al., 2006b;Bessac and Fleig, 2007; Morita et al., 2007; Wu et al., 2007;Numata et al., 2007a,b). In some cases, however, it has beenproposed that swelling induced intracellular Ca2þ rise ismediated by the same intracellular pools as those regulated byGPCR (Fischer et al., 1997). The regulatory role of Ca2þ in RVDseems to depend as well on the cell type and the identity of theosmolyte flux studied. In many cases intracellular Ca2þ seemsto be an important regulator of Kþ channels activated by cellswelling (Quesada et al., 1999; Pasantes-Morales and MoralesMulia, 2000; Wang et al., 2003a; Barfod et al., 2007). However,the channel or efflux pathway involved in Cl�/organic osmolyteloss seems to be in most cases regulated in a Ca2þ-independentmanner (Okada et al., 1994; Moran et al., 1997; Okada, 2006).A recent hypothesis, however, has postulated a role forpermissive concentrations of intracellular Ca2þ in cell volumeregulation (Szucs et al., 1996; Mongin et al., 1999; Chen et al.,2007), which might reconcile contradictory results in this area


(O’Connor and Kimelberg, 1993; Morales-Mulia et al., 1998;Mongin et al., 1999; Li et al., 2002).

Initial studies demonstrated that Ca2þ-mobilizing hormonespotentiated ionic conductances and RVD (Bender et al., 1993;Moran and Turner, 1993; Tilly et al., 1994). G-protein receptoragonists such as histamine, endothelin, norepinephrine,thrombin, bradykinin and carbachol were initially shown toaccelerate RVD after hyposmotic-swelling (Bender et al., 1993;Moran and Turner, 1993) which was demonstrated to bemediated by Cl� and Kþ efflux potentiation during RVD inaCa2þ-dependentmanner (Moran andTurner, 1993; Tilly et al.,1994; Mignen et al., 1999). Similar results are observed inastrocytes treated with ionomycin, in which isosmotic taurineefflux is not increased even when [Ca2þ]i is markedly elevatedby ionomycin. In these conditions, potentiation of theosmosensitive release of taurine was demonstrated to bemediated by the activation of calmodulin/calmodulin dependentkinase II (CaM/CaMKII) (Cardin et al., 2003). Activation ofCAMKII by H2O2 also potentiates, but doesn’t activateswelling-induced D-aspartate release in astrocytes(Haskew-Layton et al., 2005). Since then, the effect ofextracellular transmitters on the activation and/or potentiationof osmolyte flux pathways has been increasingly recognized.Activation of muscarinic receptors has been reported topotentiate D-aspartate efflux from PC12 cells after hyposmoticstimuli (Koyama et al., 2006). In SH-SY5Y neuroblastoma,potentiation of swelling-induced taurine, D-aspartate andmy-inositol release by muscarinic receptors was shown to bedependent on Ca2þ rise and PKC activation (Loveday et al.,2003). Moreover, activation of muscarinic receptors has beendemonstrated to decrease osmolyte content and inducedisosmotic cell shrinkage (Kotera and Brown, 1993; Foskettet al., 1994; Speake et al., 1998; Mozaffari and Borke, 2002)which can be followed by RVI (Sonnentag et al., 2000).Histamine-induced potentiation of swelling-activated Cl�

currents was recently demonstrated to depend on PLC andPKC activation (Zholos et al., 2005). Other signaling pathwaysindependent from intracellular Ca2þ rise, but activated byGPCRs, have been also reported to potentiate osmolytetransport. For example, activation of norepinephrine receptorspotentiates taurine release in HEK293 and cultured astrocytesin a PKA-dependent manner (Morales-Mulia et al., 2000; Moranet al., 2001). It has been widely reported that activators ofserine-threonine kinases potentiate but do not activateosmolyte efflux pathways (Jakab et al., 2002). These resultsdemonstrate that activation of GPCR (metabotropic) receptoragonists potentiate RVD and osmolyte efflux pathwaysby regulation of intracellular Ca2þ-signaling and/orserine-threonine kinases.

Adenosine triphosphate (ATP), as an agonist of purinergicreceptors, has been widely reported to modulate cell volumeregulation after hyposmotic swelling. The influence of ATP asmodulator of RVD was first described in hepatoma cells, andsalivary gland duct cells (Kim et al., 1996; Wang et al., 1996),and since then, a number of other studies have extended thisobservation while attempting to elucidate the molecularmechanisms involved in this phenomenon. Controversy stillexists as to whether ATP is acting as a necessary signal for theactivation of osmolyte efflux pathways (Wang et al., 1996;Light et al., 1999; Musante et al., 1999; Roman et al., 1999a,b;Feranchak et al., 2000; Perez-Samartin et al., 2000; Darby et al.,2003), or if its influence is only exerted once the osmolytepathways have been already activated (Van derWijk et al., 1999;Dezaki et al., 2000; Okada et al., 2001; Rubera et al., 2001;Junankar et al., 2002; Mongin andKimelberg, 2002; Franco et al.,2004b). The potential role of ATP as an autocrine signalinvolved in RVD is supported by the well-known observationthat hyposmolarity induces the release of ATP in a wide varietyof cell lines (see section above). Although there is some


controversy about the mechanism of release, it seems nowunquestionable that hyposmolarity induces ATP release.

The role of ATP in RVD has been studied primarily through:(1) the effects of exogenous ATP; (2) the use of purinergicreceptor blockers; and/or (3) the effect of agentswhich degradereleased ATP (such as apyrase) on swelling-induced osmolytefluxes. Swelling-induced ATP release has been proposed as animportant autocrine signal necessary for RVD in different celllines including human hepatocytes and hepatoma cells as well asin rat biliary and artery epithelial cells (Wang et al., 1996; Romanet al., 1999b; Feranchak et al., 2000; Shinozuka et al., 2001).The obvious ATP targets for increasing the efficiency of cellvolume regulation are the osmolyte efflux pathways, andsome studies now report ATP-induced potentiation of thevolume-activated Cl� (Wang et al., 1996; Van der Wijket al., 1999; Roman et al., 1999a,b; Feranchak et al., 2000;Perez-Samartin et al., 2000; Rubera et al., 2001; Darby et al.,2003) and Kþ channels (Dezaki et al., 2000; Light et al., 2001;Junankar et al., 2002; Soto et al., 2004; Gow et al., 2005; Haftinget al., 2006), and the osmosensitive fluxes of taurine (Musanteet al., 1999; Junankar et al., 2002; Franco, 2003; Shennan et al.,2006) and glutamate (Mongin and Kimelberg, 2002, 2005).

The question about the autocrine role of ATP in theactivation volume-sensitive osmolyte efflux pathways is stillcontroversial. Exogenous ATP and/or purinergic agonistshave been reported to activate Cl�-channels with similarcharacteristics as those of VRAC (Darby et al., 2003; Li andOlson, 2004; Zholos et al., 2005). In HTC cells and atrocytes,hydrolysis of extracellular ATP using apyrase inhibits thehypotonically activated anion currents (Wang et al., 1996;Roman et al., 1997; Roe et al., 2001; Darby et al., 2003). Inhuman epithelial intestine 407 cells and murine C127 cells,swelling-activated release of ATP was not required foractivation of Cl� currents mediated by VRAC (Hazama et al.,1999, 2000; Van der Wijk et al., 1999). In addition, exogenousATP does not elicit any taurine efflux in isosmotic conditions ineither hepatoma cells, or NIH3T3 fibroblasts (Junankar et al.,2002; Franco et al., 2004b). On the other hand, in humantracheal cells and in vivo dialisates of substantia nigra, ATPevokes an increase of taurine release in isosmotic conditions(Galietta et al., 1997; Morales et al., 2007). An effect of ATPpotentiating but not activating the hyposmotic-evoked efflux ofD-aspartate from astrocytes has also been described (Monginand Kimelberg, 2002, 2003, 2005). Swelling-activated Kþ

channels have also been reported inhibited by apyrase andpurinergic receptor antagonists in kidney cells and HTC cells(Junankar et al., 2002; Hafting et al., 2006). Although manypurinergic receptor antagonists such as suramin and PPADShave been reported to inhibit IClswell and osmolyte amino acidfluxes activated upon cell swelling, it has been suggested thatthis is due to a direct blockage of the efflux pathway (Galiettaet al., 1997; Van der Wijk et al., 1999; Junankar et al., 2002;Franco et al., 2004b). Thus, their effects should not be directlyascribed to a possible role of autocrine activation ofpurinoreceptors by released ATP during cell swelling withoutany other experimental evidence. Thus, the role ofATP-mediated autocrine signaling in RVD is still controversial.Interestingly, a recent report shows that exogenous ATPinduces amino acid osmolyte release (glutamate) in corticalastrocytes due to a transient increase in cell swelling (Takanoet al., 2005). This suggests then, that the activation of osmolyterelease by GPCR agonists such as ATP is related to a RVDresponse triggered by an increase in cell size and not due to thedirect activation of the osmosensitive signal transductionmachinery which argues against the role of autocrine signals incell volume regulation.

The ATP actions on RVD and osmolyte fluxes appear toinvolve preferentially the activation of metabotropic purinergicreceptors P2Y (Kim et al., 1996;Wang et al., 1996; Roman et al.,


1999a,b; Dezaki et al., 2000; Feranchak et al., 2000; Light et al.,2001, 2003; Shinozuka et al., 2001; Junankar et al., 2002; Darbyet al., 2003; Pafundo et al., 2004; Franco et al., 2004b; Monginand Kimelberg, 2005; Hafting et al., 2006). However, RVD wasshown to depend on CFTR mediated ATP release andautocrine signaling through both P2Y and the ionotropic P2Xreceptors in human airway epithelial cells (Braunstein et al.,2001, 2004). In addition, in human tracheal cells, released ATPafter cell swelling is hydrolyzed to adenosine, which furtherregulates Cl� channel activation via adenosine receptors(Musante et al., 1999). These results suggest that the role ofspecific purinoreceptors on RVD depends on the cell typespecific expression of the different subtypes of receptors.PhospholipaseC (PLC)-dependentCa2þ rise has been reportedto mediate the activation/potentiation of VRAC by ATP. InNIH3T3 fibroblasts potentiation of osmolyte efflux by ATPwasshown to be mediated by a PLC-induced, thapsigargin-sensitive[Ca2þ]i increase, followed by the activation of CAM/CAMKII(Franco et al., 2004b) (see Fig. 3). A similar result wassubsequently reported in cultured astrocytes where the samesignaling pathway was reported for ATP-induced potentiationof glutamate release, but in this case PKC activation wasalso involved in this phenomenon (Mongin and Kimelberg,2005).

Fig. 3. Parallel and interdependent signaling pathways arising from cellhyposmotic-inducedcellswellinghasbeenreportedtoactivateTKR(inpartactivationof theaminoacidosmolyte taurine involved inRVD.This effect isOtherpossible intermediates are thesmallG-protein rhoandtherho-depemediated by stretch or by its transactivation by other signaling cascades inreactiveoxygenspecies(Varelaetal.,2004;Francoetal.,2004b).Ontheotheor sensitivity of the taurine release pathway by activation of calmodulin ((althougharoleofhyposmotic-inducedATPrelease isnotdiscarded)was shreceptors (Franco et al., 2004b).A crosstalk of these two interdependent pactivatePLCgthroughitstyrosinephosphorylation.Similarly,P2Yreceptotrimers. Inhibition of both pathways completely abolishes the osmosensitreceptors; FAK, focal adhesion kinase; ROS, reactive oxygen species; PI3Ktransporters.


Activation of leukotriene and prostaglandin receptors hasalso been shown to regulate RVD and osmolyte efflux.Leukotriene D4 (LTD4) induces isosmotic cell shrinkage andpotentiates RVD and osmolyte loss after hypotonic exposure(Lambert, 1987, 1989; Lambert et al., 1987; Lambert andHoffmann, 1993; Hoffmann and Hougaard, 2001) in aCa2þ-independent manner (Jorgensen et al., 1996). In contrast,LTD4-induced stimulation of RVD in mouse distal colon cryptswas proposed to be Ca2þ-dependent (Mignen et al., 1999). Thepotential role of LTD4 release as an autocrine signal in RVD issupported by the observed inhibition of RVDby leukotrieneD4receptor antagonists (Diener and Scharrer, 1993; Diener andGartmann, 1994). Activation of prostaglandin receptors byPGE2 also stimulates RVD in ciliary epithelial cells (Civan et al.,1992). Stimulation of taurine release in murine fibroblasts byPGE1 was shown to be mediated by cAMP and PKA-dependentmechanisms (Heacock et al., 2006b). Similarly, activation oflysophospholipid receptors has been implicated in theregulation of cell volume regulatory pathways.Lysophosphatidic acid (LPA) potentiates Ca2þ-rise afterhypotonic stress in cultured lens epithelial cells (Ohata et al.,1999). Interestingly, both hyposmolarity and LPA were shownto activate similar tyrosine kinase-dependent signalingpathways (Hirakawa et al., 2006). Finally, activation of

swelling and their role in osmolyte efflux. In NIH3T3 fibroblasts,icular,theepidermalgrowthfactorreceptorEGFR),whichregulatethemediatedbythe intermediateactivationofPI3K(Francoetal., 2004a).ndentkinase (ROCK). In theseconditions, activationofEGFRmightbecluding the integrin/FAK system, stress activated kinases (p38) and/orrhand, intracellularCa2RrisehasbeenshowntoregulatetheefficiencyCAM)/calmodulin-dependent kinase II (CAMKII). Exogenous ATPowntomodulate this pathwaybyactivationofpurinergic (P2Y2/P2Y4)arallel pathways is showed in dashed arrows. TKRshavebeen shown torshavebeenreportedtoactivatePI3KthroughbgsubunitsofG-proteinive release of taurine (Franco et al., 2004b). TKR, tyrosine kinase, phophatidyl inositide-3 kinase; ABC-T, ATP-binding cassette


sphingosine 1-phosphate and LPA receptors were recentlydemonstrated to potentiate taurine release in aCa2þ-dependent and PKC-dependent manner (Heacocket al., 2006a).

Activation of other distinctGPCRs has beenwidely reportedto regulate osmolyte fluxes. For example, thrombin receptoraccelerates RVD after hyposmotic-swelling (Bender et al.,1993) which was demonstrated to be mediated by Cl� effluxpotentiation during RVD (Tilly et al., 1994; Klausen et al., 2006)in a Ca2þ-independent manner (Manolopoulos et al., 1997a).On the other hand, thrombin receptor activation by itselfactivates organic osmolyte (amino acid) release (Manolopouloset al., 1997b) an effect reported to be mediated by Ca2þ-dependent and independent mechanisms (Cheema et al., 2007,2005; Ramos-Mandujano et al., 2007). TheG-protein coupled Ca2þ-receptor was recently demonstratedto modulate the Cl� conductance activated by cell swellingthrough a cAMP dependent pathway (Shimizu et al., 2000). Alltogether, these results suggest that activation of GPCRs canregulate the cell volume regulatory process by two distinctmechanisms.WhileGPCR activation has been demonstrated todirectly activate Ca2þ-dependent Kþ-channels, it regulates theactivity of the Cl� and osmolyte efflux pathway(s) byaugmenting its effectiveness and/or sensitivity to osmolarity,by activation of serine/threonine kinases including PKC, PKAand/or CaM/CaMKII.

Tyrosine kinase receptors

Tyrosine phosphorylation events have been widely reported toparticipate in the activation/regulation of RVD. Indeed tyrosinekinases regulate both Cl� and organic osmolyte release afterswelling in a wide variety of cell types (Jakab et al., 2002;Pasantes-Morales and Franco, 2002; de La Paz et al., 2002;Wehner et al., 2003; Pasantes-Morales et al., 2006a). It has beenwidely described how general inhibitors of tyrosinephosphorylation such as herbimycin, lavendustin andtyrphostins, prevent the activation of Cl� and organic osmolyterelease, while inhibition of protein tyrosine phosphatasespotentiates the activation of these efflux pathways (Jakab et al.,2002; Pasantes-Morales and Franco, 2002;Wehner et al., 2003).The molecular identities of the tyrosine kinases involved in theregulation of Cl� and organic osmolyte release are unclear. Sofar, different candidates have been proposed including differentmembers of the src family of tyrosine kinases (such as src, syk,lyn and lck) (Lepple-Wienhues et al., 1998; Musch et al., 1999;Hubert et al., 2000; Browe and Baumgarten, 2003; Walsh andZhang, 2005; Vazquez-Juarez et al., 2008); and the focaladhesion kinase (FAK) (Tilly et al., 1996; Browe andBaumgarten, 2003; Walsh and Zhang, 2005; Lezama et al.,2005b). Other tyrosine phosphorylation-dependent signalingpathways have also been proposed to participate in thesephenomenon including the phosphatidyl-inositide 3-kinase(PI3K) (Tilly et al., 1996; Feranchak et al., 1998; Morales-Muliaet al., 2001; Shi et al., 2002; de La Paz et al., 2002; Wang et al.,2004; Franco et al., 2004a, 2001; Ren et al., 2008), and themitogen-activated (ERK1/ERK2) and stress-activated proteinkinases (JNK and p38) (Crepel et al., 1998; Shen et al., 2001;vom Dahl et al., 2003; Franco et al., 2004b; Pan et al., 2007). Inany case, the role of these signaling pathways seems to varyaccording to the cell type studied. In addition, the exactmechanism or the osmosensor involved in the activation oftyrosine phosphorylation signaling upon cell swelling is also stillelusive.

Growth factor (or cytokine) signaling through the activationof receptors coupled to an intrinsic tyrosine kinase domain(TKR) is an important regulator of cellular signaling. Growthfactor receptor signaling has been recently reported to regulate


cell volume regulation. Insulin and epidermal growth factor(EGF) have been reported to stimulate RVD, osmolyte andionic fluxes upon hyposmotic shock (Tilly et al., 1993; Miyauchiet al., 2000; Shi et al., 2002; Abdullaev et al., 2003; Franco et al.,2004a; Lezama et al., 2005b). Moreover, agonistic stimulation oftyrosine kinase receptors activates osmolyte efflux in theabsence of cell swelling (Tilly et al., 1993; Bali et al., 2001; Varelaet al., 2004; Franco et al., 2004a; Browe and Baumgarten, 2006).Accordingly, inhibition of EGFR has been reported to inhibitswelling-induced Cl� and taurine release (Du et al., 2004;Franco et al., 2004a; Ren and Baumgarten, 2005; Lezama et al.,2005b; Browe and Baumgarten, 2006; Ren et al., 2008). Finally,activation of EGFR receptor has also been shown to modulateosmolyte fluxes and RVD by activation of PI3K and ROSformation (Varela et al., 2004; Franco et al., 2004a; Browe andBaumgarten, 2006; Ren et al., 2008).

Membrane Receptors as Cell Volume Sensors

Previous reports demonstrate that mechanical stress caninduce plasma membrane receptor activation in the absence ofligand binding, suggesting that plasma membrane receptorsmight function as important mechano-transducers (see Fig. 4).In this way, it has been postulated that TKR can be activated in aligand-independent manner by mechanical stress. This has beenpostulated to be mediated by increases in the elongation andfluidity of the plasma membrane which results in the exposureof tyrosine kinase domains that allow TKR autophosphorylation(Hu et al., 1998; Li and Xu, 2000; Cheng et al., 2002;Correa-Meyer et al., 2002; Li and Xu, 2007). Franco andcoworkers recently reported the activation of TKR in responseto cell swelling (Franco et al., 2004a). This, was subsequentlyconfirmed in other experimental models of RVD afterhyposmotic swelling (Lezama et al., 2005a,b; Pasantes-Moraleset al., 2006a). For example, activation of the ErbB4 tyrosinekinase receptor (a member of the EGFR family) was reportedto occur in cerebellar granule neurons after hyposmoticswelling (Lezama et al., 2005b). Hyposmotically inducedligand-independent activation of EGFR was also demonstratedin epithelial cells (Taruno et al., 2007). Finally, activation of TKRwas shown also to be induced by its transactivation throughother signaling cascades (Moro et al., 1998; Zwick et al., 1999).In this way, stretch induced transactivation of EGFR has beenreported mediated by integrins and/or GPCRs (Browe andBaumgarten, 2006).

G-protein coupled receptors may be also directly activatedby cellular swelling or stretch. In endothelial cells hypotonicstress has been demonstrated to activate the bradykinin B2GPCR in a ligand-independent form (Chachisvilis et al., 2006).On the other hand, hypotonicity increases muscarinic receptorcurrent in gastric myocytes by modification of the actinmicrofilament structure (Li et al., 2002; Wang et al., 2003b).Additionally, hyposmolarity also directly activates PLCd(known to be coupled to GPCR) but the mechanism is stillunknown. Other potential plasma membrane receptors thathave been proposed as candidates for cell volume sensorsare integrins. Swelling- or stretch-induced integrin activationhas been widely reported (Ingber, 1997, 2006; Browe andBaumgarten, 2003). Integrin inhibitory peptides have beenreported to block RVD by inhibition of the integrin–src–MAPKsignaling pathway (vomDahl et al., 2003). Anti-integrin antibodyagainst the alpha-5-beta-1 dimer inhibits tyrosine kinaseactivation induced by hypotonic stimuli (Hirakawa et al., 2006).Integrin stimulation has also been shown to stimulateswelling-activated Ca2þ-rise and distinct signal transductionpathways (Miyauchi et al., 2006). These results suggest apotential role of plasma membrane receptors as volumesensors involved in cell volume recovery after cell swelling or

Fig. 4. Ligand-independent activationofplasmamembrane receptors by cell swelling, a role as volume sensors.Cell swellingor stretchhasbeenlargely reported toactivateplasmamembrane receptors suchas integrins, TKRandGPCR in a ligand-independentmanner. In addition, IntegrinsandGPCR activation has been shown to transactivate TKR by the activation of src or PKC signaling cascades. Although cell swelling can activatethese receptorsbyplasmamembrane stretchor regulationof cellular cytoskeleton,other signalingcascadesmightbe involved in theactivationofthesesignalingmoleculesinaligand-independentmanner.TheseincludeROSandactivationofthestressactivatedkinasep38.Finally, integrinsandGPCR can transactivate downstream signals of the TKR such as PI3K (Moro et al., 1998; Zwick et al., 1999; Gschwind et al., 2001; Liu et al., 2004;Varela et al., 2004; Franco et al., 2004a; Lezama et al., 2005b; Browe and Baumgarten, 2006). TKR, tyrosine kinase receptors; GPCR, G-proteincoupled receptors; FAK, focal adhesion kinase; ROS, reactive oxygen species; PI3K, phophatidyl inositide-3 kinase.


RVD. Activation of these receptors might also be potentiatedby released hormones during cell swelling.

Interdependent Signals Regulating Osmolyte Transport

Wehner et al. (2003) initially proposed that in order to studythe signal transduction cascades involved in cell volumeregulation, it should be considered that cell volume changes aresensed and transduced through a complex array of distinctinterdependent signals. As summarized above, osmolyte fluxes,particularly those of Cl� and organic anions such as taurine,seem to be regulated by both Ca2þ-dependent and tyrosinephosphorylation-dependent signaling cascades. Cell swellinghas been also demonstrated to regulate the activation of plasmamembrane receptors such as GPCR, TKR and integrins byligand-dependent or independent mechanisms. From thestudies mentioned above we hypothesize that at least twodistinct interdependent signaling pathways regulate and activatethe osmolyte efflux pathways involved in RVD (see Fig. 5).Tyrosine kinases and tyrosine phophorylation-dependentsignals seem to be involved in the activation of Cl� and organicosmolyte fluxes during RVD in most cell types studies (Tillyet al., 1993; Jakab et al., 2002; Pasantes-Morales and Franco,2002;Wehner et al., 2003; Pasantes-Morales et al., 2006a). Thismight involve the activation of distinct signaling enzymesregulated by tyrosine phosphorylation events such assrc-kinases, FAK, MAPK or PI3K. These pathways have beenreported to be triggered and/or regulated by the activation ofgrowth factor receptors or integrins in a ligand independentmanner (vomDahl et al., 2003; Varela et al., 2004; Franco et al.,2004a; Lezama et al., 2005a; Browe and Baumgarten, 2006;Taruno et al., 2007).

On the other hand, activation of swelling-induced Cl� andorganic osmolyte release has been demonstrated to be largely


independent from rises in intracellular Ca2þ. However,in most cases, GPCR agonist-induced potentiation ofintracellular Ca2þ rise increases the efflux of these osmolytes,an effect that is also mimicked by the use of Ca2þ-ionophores(Junankar et al., 2002; Mongin and Kimelberg, 2002, 2005;Cardin et al., 2003; Loveday et al., 2003; Franco et al., 2004b).These results, together with the observation that apermissive Ca2þ concentration is necessary for both RVD andthe activation of Cl�/organic osmolyte release (Szucs et al.,1996; Mongin et al., 1999; Park et al., 2007), suggest a regulatoryrole for intracellular Ca2þ in the activation of these pathways.The mechanisms involved in this phenomenon are still unclear,however, a recent report by Falktoft and Lambert (2004)showed that agonist-induced increase in intracellularCa2þ prior to the induction of cell swelling still potentiatesRVD and osmolyte efflux, even though the intracellular Ca2þ

concentration has already returned to basal conditions at themoment of the swelling-induced stimulus. Similar results areobserved when Ca2þ-dependent signaling enzymes arestimulated prior to the hypotonic stimulus, including PKCactivation with phorbol esters (Falktoft and Lambert, 2004).Thus, we suggest that Ca2þmight regulate either the sensitivityof the osmosensitive machinery to changes in cell volume,or the availability of osmolyte efflux pathways in the plasmamembrane. For the case of swelling-activated Kþ channels,evidence so far suggests that Ca2þ has a direct activationeffect when Ca2þ-activated Kþ channels are involved(Pasantes-Morales andMorales Mulia, 2000;Wang et al., 2003a;Barfod et al., 2007). A strong possibility also exist that Ca2þ andtyrosine kinases activate distinct osmolyte efflux pathways,however, the observations that both Ca2þ and tyrosinephosphorylation regulated fluxes are in most cases similarlyinhibited or sensitive to the same ion channel blockers seems toargue against this hypothesis (Feranchak et al., 2000;

Fig. 5. Interdependent signals regulating osmolyte transport.We hypothesize that at least two distinct interdependent signaling regulate andactivate the osmolyte efflux pathways involved in RVD. Activation of growth factor receptors or integrins (vom Dahl et al., 2003; Varela et al.,2004; Franco et al., 2004a; Lezama et al., 2005a; Browe and Baumgarten, 2006; Taruno et al., 2007) coupled to tyrosine kinases and tyrosinephophorylation-dependent signals seem to be involved in the activation of Cl� and organic osmolyte fluxes during RVD inmost cell types studies.This might involve the activation of distinct signaling enzymes regulated by tyrosine phosphorylation events such as src-kinases, FAK, MAPK orPI3K (Tilly et al., 1993; Jakab et al., 2002; Pasantes-Morales and Franco, 2002; de La Paz et al., 2002;Wehner et al., 2003;Hoffmann andPedersen,2006; Alexander andGrinstein, 2006a; Pasantes-Morales et al., 2006a). On the other hand, GPCR-induced regulation of swelling-inducedCl� andorganic osmolyte release has been demonstrated to be largely dependent from rises in intracellular Ca2R (Junankar et al., 2002; Mongin andKimelberg, 2002, 2005; Cardin et al., 2003; Loveday et al., 2003; Franco et al., 2004b)which suggests a regulatory role for intracellular Ca2R in theactivation of these pathways. Together, these results suggest that Ca2R might regulate either the sensitivity of the osmosensitive machinery tochanges in cell volumeor theavailabilityofosmolytepathways in theplasmamembrane. In thecaseof swelling-activatedKRchannels, evidence sofarsuggests thatCa2RonlyhasadirectactivationeffectwhenCa2R-activatedKRchannelsare involved(Pasantes-MoralesandMoralesMulia,2000;Wang et al., 2003a; Barfod et al., 2007), however, Ca2R-independent KR channels have also been reported to participate in RVD. AlthoughbothCa2R-andtyrosinekinase-dependentsignalsseemtobeinterdependentandtorunparallelduringosmo-mechanotransductionit is importanttomention that a cross talk of both signaling cascadesmight exist which will explain contradictory results. GPCRs can either transactivate TKRdirectly or activate similar tyrosine phosphorylation-dependent pathways such as PI3K. Similarly, TKR stimulation can also activate PLCg by itstyrosine phosphorylationwhich triggers Ca2R-dependent signaling pathways.We consider that in order for these osmolyte efflux pathways to beefficiently activated both signaling cascades must be triggered. TKR, tyrosine kinase receptors; GPCR, G-protein coupled receptors; FAK, focaladhesion kinase; ROS, reactive oxygen species; PI3K, phophatidyl inositide-3 kinase; PLC, phospholipase C; MAPK, mitogen-activated proteinkinases;AC,adenylatecyclase;cAMP,cyclicadenosinemonophosphate;PKA,proteinkinaseA;CaM,calmodulin;CAMKII,calmodulin-dependentkinase II.


Darby et al., 2003; Falktoft and Lambert, 2004; Franco et al.,2004b).

Although both Ca2þ- and tyrosine kinase-signals seemto be interdependent but to run in parallel duringosmo-mechanotransduction, it is important to mention that across talk between both signaling cascades might exist, whichwill explain contradictory observations. As shown in Figures 4and 5, activation ofGPCRs can either transactivate TKRdirectlyor activate similar tyrosine phosphorylation-dependentpathways such as PI3K. Similarly, TKR activation can alsoactivate PLCg by tyrosine phosphorylation and mediateCa2þ-dependent pathways. As mentioned above, agonist


stimulation of either GPCRs or TKR has been reported to haveconflicting results on the direct activation and/or regulation ofosmolyte efflux pathways. In some cases activation of thesereceptors does not elicit osmolyte efflux by itself, but in othersit does activate the efflux pathways. We consider that in orderfor these pathways to be efficiently activated, both signalingcascades must be triggered. In some cell types, activationof Ca2þ-dependent signals by GPCR might not mediatetransactivation of tyrosine kinase-dependent signals while inothers itmight do so. Similar considerations can exist in the caseof TKR. A potential candidate of crosstalk and convergence forboth GPCR/Ca2þ-dependent and TKR/integrins-tyrosine


phosphorylation-dependent signaling during cell swelling isPLCgwhich has been reported to be activated in hyposmolarityby tyrosine phsophorylation and to be required for RVD andosmolyte efflux activation (Moore et al., 2002; Barfod et al.,2005; Nam et al., 2007; Varela et al., 2007). This hypothesis isconfirmed by recent studies inNIH3T3 cells (see Fig. 3) (Francoet al., 2004a,b). In this work, swelling-induced osmolyte releasewas shown to be strongly potentiated by ATP (GPCR agonist)and EGF (TKR agonist). However, these agonists by themselvesdo not elicit osmolyte release (for the case of ATP) or justslightly activate osmolyte efflux (for the case of EGF). For thecase of EGF-induced osmolyte release, the magnitude ofactivation does not compare to the same extent as that inducedby cell swelling. Regulation of osmolyte release by EGFRsignaling is highly dependent on tyrosine phosphorylation andPI3K, while that of ATP is Ca2þ dependent. Thus, inhibition ofboth pathways completely abolishes osmolyte release. On theother hand, activation of thrombin-activated GPCRs elicits arobust osmolyte response in astrocytes, which is mediated bythe simultaneous activation of the Ca2þ-PLC-CAM/CAMKIIand the EGFR-PI3K-tyrosine kinase signaling pathways(Cheema et al., 2005; Ramos-Mandujano et al., 2007;Vazquez-Juarez et al., 2008).

The Role of Changes in the Extracellular Space Volume

Asmentioned above, contradictory results have been observedabout the role of released neurotransmitters on the regulationof the osmolyte transport mechanisms involved in cell volumeregulation. However a distinction must be drawn whencomparing in vitro studies of cultured cells against morephysiological conditions in integrated systems. In cell culturestudies factors such as the dilution of released transmitters intoan almost infinite extracellular space and/or the rapid hydrolysisof released signaling molecules might play an important role inthe underestimation of the role of released transmitters incell volume regulation. A recent report with an improvedmethodology to assess secreted ATP has demonstrated that inthe apical surface of human airway epithelia, swelling-inducedATP release raises the levels of extracellular ATP to themagnitude necessary to activate P2Y2 receptors that facilitatecell volume regulation (Okada et al., 2006). For example, duringanoxia and/or ischemia, cell swelling occurs in the brain andspinal cord. This has been shown paralleled by a reduction in theextracellular space that leads to a greater accumulation of ionsand neuroactive substances (Sykova, 2001, 2004). Similarresults have been reported during epilepsy, where epileptiformdischarges are followed by a reduction in the extracellular space(Kilb et al., 2006; Olsson et al., 2006). In such conditions ofreduced extracellular space, ATP and other transmitters havebeen shown to be released and thus might act as importantmodulators of cell volume regulation under these conditions.

The Role of Transmitter Release Induced by CellVolume Changes in Cell Function

Swelling-induced transmitter secretion has been proposed tohave important pathophysiological implications. For example,peptides released after swelling could play an important role inthe pathophysiology of ischemia as mediators of local/remoteprotective preconditioning. The magnitude of EAA releaseduring ischemic events may be also sufficient to exacerbateneuronal damage. For instance, early cellular swelling duringischemia has been reported to be mediated by EAA releasethrough Ca2þ-dependent exocytosis (Katayama et al., 1992).Similar observations have been recently reported in humancolon cancer cells where hypostomic-induced ATP releaseactivates an autocrine/paracrine cell death pathway byactivation of purinergic receptors (Selzner et al., 2004). In


addition, an interestingmodel has been recently described in ratretina glial cells where EAA and ATP release exert a protectiveeffect against ischemic-induced cell swelling by activation ofPKA-dependent Kþ and Cl� conductances (Uckermann et al.,2006). Finally, hypotonicity-induced ATP release has also beenimplicated in growth stimulation of prostate cancer cells(Nandigama et al., 2006) and paracrine osteoblast activation(Romanello et al., 2005). Autocrine and paracrine activation ofhuman osteoblasts has been reported to be induced byswelling-induced ATP release (Romanello et al., 2005). Theseresults demonstrate that released transmitters can have bothdeleterious and protective effects in the surrounding tissue/organ environment by regulating cell volume or by activation ofother signaling process leading to cellular death, proliferation ordifferentiation which strengthens their physiologicalimportance.

Conclusions and Perspectives

Cell volume regulation is a transcendental homeostaticphenomenon for the normal physiology of cells andconsequently, for the proper function of organs and tissues. Alarge amount of effort has been focused on the characterizationof osmolyte flux pathways (channels, transporters and pumps)and signal transduction cascades involved in cells’ volumeregulation after cell swelling. Recent reports have suggested animportant role for released transmitters and plasmamembranereceptors in this phenomenon. Activation of plasmamembranereceptors in a ligand-dependent (by released transmitters) or-independent manner (by cell stretch or transactivation) hasbeen shown to regulate specific signaling cascades involved ineither the activation or modulation of the osmolyte fluxesinvolved in the volume recovery phase. The evidence so farpoints to a distinction between those signaling cascades thatactivate osmolyte release pathways, and those involved in themodulation of the osmolyte transport efficiency. Whiletyrosine phophorylation events seem to be necessary for theactivation of osmolyte transport, Ca2þ signaling pathways havebeen proposed as modulators of these pathways’ efficiency.However, the precise mechanisms by which these signalingevents converge and regulate cell volume constancy remainlargely elusive. Possible candidates might involve direct targetphosphorylation and/or channel/transporter insertionmechanisms. In any case, it is now obvious that a complexsensory system should involve the parallel activation ofinterdependent signaling cascades regulating cell volume.

On the other hand controversy exists, particularly regardingthe proposed role of autocrine signals in cell volume regulation.This discrepancy might be reconciled by the fact that in in vitroexperimental systems of cells in culture, dilution of releasedtransmitters into an almost infinite extracellular space andrapid hydrolysis of released signaling molecules might play animportant role in the underestimation of the role of releasedtransmitters in cell volume regulation. In addition, cellularswelling in vivo might be paralleled by a reduction in theextracellular space volume which will increase theaccumulation of transmitters and potentiate their autocrinesignaling role. Thus, the elucidation of the mechanisms involvedin transmitter release and the regulation/activation of plasmamembrane receptors during cell swelling is of greatphysiological importance to understand either the protectiveor deleterious effects of both released transmitters and changesin cell volume in vivo.

Acknowledgments

This work was supported [in part] by the Intramural ResearchProgramof theNIH/National Institute of Environmental HealthSciences (Franco R), andUCMEXUS-CONACYT Postdoctoral


Fellowship Program (Ochoa-de la Paz, LD). We appreciate theNIH Fellows Editorial Board for its constructive comments onthe manuscript. We apologize to our colleagues for all thosestudies not cited in this review due to space limitations.

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