chloride channelopathies
TRANSCRIPT
Hafez M. BazaraaMMXXI
Chloride channelopathies
l Na depolarisationl K repolarisationElectrochemical concordance è effluxThen Na/K pump è influx
Na: least permeability
l Calcium (slow) depolarisationl Chloride (muscle) repolarisationConc è INElectric è OUT (=in at -70mV)↑ permeability è stabilization effect
Na: least permeability
l CHANNELSPassive ion pores
l CO-TRANSPORTERS
SymportersAntiporters (exchangers)
l PUMPSActive
transporters(ATP)
Basolateral active Na/K exchange(most renal energy)
Apical Na transportl Follows conc. gradientl Secondary transporters-Na coupled cotransport-ENaC-Na/H exchanger
Loudon & Fry. Ann Clin Biochem. 2014
Loudon & Fry. Ann Clin Biochem. 2014
Bartter syndrome
Renal salt wasting
↑ renin, aldosterone
HypoK metabolic alkalosis
Expressed in inner ear
Gitelman syndrome
l SLC2A3 mutation è NCCT thiazide sensitive NaCl cotransporter
l ClCNKB mutation è ClC-KB
Na Cl Mg K (ALD) wasting↓Mg è ↓Ca (PTH)
PCT receptor-mediated endocytosis
Electrogenic vacuolar
H ATPase
ClC-5HHHH
HHHH+Cl- ClClCl
Apical
Endosome
ClC-5
l Kidneys (mainly PCT) & Intestinel Cl/H exchanger, apical endosomesl Maintains acidification/ activationl Cl dissipates high +ve intraluminal potential
ClC-5: Dent’s disease (XLR)
l Filtered LMW proteins è PCT endocytosisXXXX LMW tubular proteinuriaα1-microglobulinuria to microalbuminuria close to or above 1
l PTH & bound vit D è endocytosisXXXX ↑ PTH & ↑ Vit D activationHyperphosphaturia, hypercalcuria, stones & NCRenal glucosuria, aminoaciduria
l CLCN5 gene mutation è Dent’s disease type Il OCRL1 gene mutation è Dent’s disease type IIl . è Lowe syndrome
Inositol Polyphosphate-5-Phosphatase
Involved in regulating membrane traffickingNumerous subcellular locations including endosomes & plasma membrane. May also play a role in primary cilium formation.
l Electrical activity– Voltage-gated– Ligand-gated GABA, Gly
l Salt transport– Renal– CFTR, , SLC26A3
l Intracellular Cl/H exch. (organoids)– Dent– Storage
EXTRA-RENAL
l Electrical activity– Voltage-gated– Ligand-gated GABA, Gly
l Salt transport– Renal– CFTR , SLC26A3
l Intracellular Cl/H exch. (organoids)– Dent– Storage
Voltage-gated ClC-0 cloned (1990)
l Torpedo marmorata
è ClCN genes coding ClC proteins-Plasma membrane channels-Cl/H exchangers NOT strictly channelopathies
Myotonia
Myotonia congenita
AD ThomsenAR Becker
l ClC1 in skeletal musclel Voltage-gated Cl channell Repolarisation & stabilization
l Chloride (muscle) repolarisationConc è INElectric è OUT (=in at -70mV)↑ permeability è stabilization effect
Ligand-gated Cl channelopathies
ClC-2l CNS: GABA-A receptors è ↑ intracellular Cl è Inhibitory
Proposed relation to epilepsy (3q26)l Widely expressed
Unproven relation to lung development, gastric secretionl Mice: leukoencephalopathy, blindness, testicular
degeneration
Ligand-gated Cl channelopathies
Hereditary hyperekplexia (stiff baby syndrome)l ↑ startle response to mild stimuli (visual, aud.,
tactile)l Hypertonia (during no voluntary movement possible)l Laryngospasm, apnea may occur. ?SIDSl Glycine-mediated (GLRA1 mutation)
EXTRA-RENAL
l Electrical activity– Voltage-gated– Ligand-gated GABA, Gly
l Salt transport– Renal– CFTR , SLC26A3
l Intracellular Cl/H exch. (organoids)– Dent– Storage
ClC-7
l Widely expressed, lysosomesl Osteopetrosis (polymorphisms BMD)l Lysosomal storage & neurodegenerationl Retinal degeneration
EXTRA-RENALl Electrical activity
– Voltage-gated– Ligand-gated GABA, Gly
l Salt transport– Renal– CFTR, SLC26A3
l Intracellular Cl/H exch. (organoids)– Dent– Storage
CFTR
C F Transmembrane (conductance) Regulator
Phosphorylation-dependent (cAMP) apical Cl channell The most common hereditary lethal disease in Caucasians
(1:3000)l Abnormal epithelial salt/ water transportl ENaC dys(up)regulationl Resp., enterocytes, gland acini, pancreas, vas deferens, …
CFTR (lung ionocytes)
Abnormal CFTR allows Cl influx but not efflux↓ Cl, Na, H2O in secretions
Congenital Chloride (losing) Diarrhea
l Solute linked carrier
SLC26A3 Membrane anion exchanger
Congenital Chloride (losing) Diarrhea
l Solute linked carrier SLC26A3Membrane anion (Cl/HCO3 exchanger)
l Watery diarrhea with low pH & high Cl contentl Hypochloremic metabolic alkalosisBUTYRATE:↑ intestinal water and ion absorption through a variety of
mechanisms, including the activation of a parallel Cl-/butyrate and Na+/H+ exchanger.
New targeted therapies may be under way….
l Mexiletene & Lamotrigine: Voltage-gated Na channel blockers. Proposed for myotonia.
l Targets F508 deletion in CF:The newly approved medication combines two “corrector” molecules (elexacaftor and tezacaftor) that address protein misfolding plus a “potentiator” (ivacaftor) that improves chloride channel opening.
CONCLUSION
l Don’t overlook anionsl Chloride transport:
– Salt & water reabsorption– Epithelial salt & water transport– Electrical activity– Endosome & Lysosome function
l There’s a lot we don’t know
Q1
A zeroB inwards according to concentration gradientC outwards according to electrical gradient D outwards by active transport
Under basal (resting) conditions, the net movement of chloride ions across the cell membrane is
Q2
A Bartter syndromeB Nephrogenic diabetes incipidus C Myotonia congenitaD Cystic fibrosis
Disorders of chloride channels/ chloride transport are implicated in the following conditions EXCEPT
Q3
A the presence of abnormal proteins in plasmaB increased glomerular permeability C impaired tubular reabsorptionD losses from the urinary tract
The main mechanism of proteinuria in Dent disease is