Lack of pendrin HCO 3 − transport elevates vestibular endolymphatic [Ca 2+ ] by inhibition of acid-sensitive TRPV5 and TRPV6 channels

• Published in: American journal of physiology. Renal physiology 2007-05, Vol.292 (5), p.F1314-F1321
• Main Authors: Nakaya, Kazuhiro, Harbidge, Donald G., Wangemann, Philine, Schultz, Bruce D., Green, Eric D., Wall, Susan M., Marcus, Daniel C.
• Format: Article
• Language: English
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00432.2006

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.