Lack of pendrin HCO3- transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels.
The low Ca(2+) concentration ([Ca(2+)]) of mammalian endolymph in the inner ear is required for normal hearing and balance. We reported (Yamauchi et al., Biochem Biophys Res Commun 331: 1353-1357, 2005) that the epithelial Ca(2+) channels TRPV5 and TRPV6 (transient receptor potential types 5 and 6) are expressed in the vestibular system and that TRPV5 expression is stimulated by 1,25-dihydroxyvitamin D(3), as also reported in kidney. TRPV5/6 channels are known to be inhibited by extracellular acidic pH. Endolymphatic pH, [Ca(2+)], and transepithelial potential of the utricle were measured in Cl(-)/HCO(3)(-) exchanger pendrin (SLC26A4) knockout mice in vivo. Slc26a4(-/-) mice exhibit reduced pH and utricular endolymphatic potential and increased [Ca(2+)]. Monolayers of primary cultures of rat semicircular canal duct cells were grown on permeable supports, and cellular uptake of (45)Ca(2+) was measured individually from the apical and basolateral sides. Net uptake of (45)Ca(2+) was greater after incubation with 1,25-dihydroxyvitamin D(3). Net (45)Ca(2+) absorption was dramatically inhibited by low apical pH and was stimulated by apical alkaline pH. Gadolinium, lanthanum, and ruthenium red reduced apical uptake. These observations support the notion that one aspect of vestibular dysfunction in Pendred syndrome is a pathological elevation of endolymphatic [Ca(2+)] due to luminal acidification and consequent inhibition of TRPV5/6-mediated Ca(2+) absorption.
Nakaya
Kazuhiro
K
Cellular Biophysics Laboratory, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506-5802, USA.
Harbidge
Donald G
DG
Wangemann
Philine
P
Schultz
Bruce D
BD
Green
Eric D
ED
Wall
Susan M
SM
Marcus
Daniel C
DC
D000042:Absorption / Q000187:drug effects; D000143:Acids / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency*; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000172:deficiency*; D004594:Electrophysiology; D004711:Endolymphatic Duct / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D012444:Saccule and Utricle / Q000378:metabolism / Q000503:physiopathology; D012665:Semicircular Canals / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000076988:Sulfate Transporters; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
D000143:Acids; D027321:Anion Transport Proteins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D027963:Chloride-Bicarbonate Antiporters; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C446923:Trpv6 protein, mouse; D002117:Calcitriol; D002118:Calcium