Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules.
The CLC gene family encodes Cl(-) channels or Cl(-)/H(+) exchangers. While our understanding of their structure-function relationship has greatly benefited from the crystal structure of bacterial homologues, human inherited diseases and knock-out mice were crucial in deciphering their physiological roles. Several vesicular CLC Cl(-)/H(+) exchangers are expressed in the proximal tubule (PT). ClC-5 mutations cause Dent's disease which is associated with low molecular weight proteinuria and kidney stones. ClC-5 knock-out mice revealed impaired endocytosis as the primary defect in Dent's disease. It extends to receptor-mediated and fluid-phase endocytosis and entails changes in calciotropic hormones that result in kidney stones. No renal functions could be assigned so far to ClC-3 and ClC-4, which are also expressed in PTs. Loss of ClC-7 or its beta-subunit Ostm1 entails lysosomal storage in the PT, in addition to the neuronal lysosomal storage and osteopetrosis that are the hallmarks of ClC-7/Ostm1 loss in mice and men.
Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
Vanessa
V
Plans
Gesa
G
Rickheit
Thomas J
TJ
Jentsch
D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D053565:Hypercalciuria / Q000209:etiology; D007015:Hypophosphatemia, Familial / Q000209:etiology; D007669:Kidney Calculi / Q000209:etiology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout
C097503:CLC-5 chloride channel; C097540:CLCN7 protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; C509143:OSTM1 protein, mouse