title: Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model.
abstract: Pendred syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to determine how loss of pendrin leads to hair cell degeneration and deafness. We evaluated pendrin function by ratiometric microfluorometry, hearing by auditory brain stem recordings, and expression of K(+) and Ca(2+) channels by confocal immunohistochemistry. Cochlear pH and Ca(2+) concentrations and endocochlear potential (EP) were measured with double-barreled ion-selective microelectrodes. Pendrin in the cochlea was characterized as a formate-permeable and DIDS-sensitive anion exchanger that is likely to mediate HCO(3)(-) secretion into endolymph. Hence endolymph in Slc26a4(+/-) mice was more alkaline than perilymph, and the loss of pendrin in Slc26a4(-/-) mice led to an acidification of endolymph. The stria vascularis of Slc26a4(-/-) mice expressed the K(+) channel Kcnj10 and generated a small endocochlear potential before the normal onset of hearing at postnatal day 12. This small potential and the expression of Kcnj10 were lost during further development, and Slc26a4(-/-) mice did not acquire hearing. Endolymphatic acidification may be responsible for inhibition of Ca(2+) reabsorption from endolymph via the acid-sensitive epithelial Ca(2+) channels Trpv5 and Trpv6. Hence the endolymphatic Ca(2+) concentration was found elevated in Slc26a4(-/-) mice. This elevation may inhibit sensory transduction necessary for hearing and promote the degeneration of the sensory hair cells. Degeneration of the hair cells closes a window of opportunity to restore the normal development of hearing in Slc26a4(-/-) mice and possibly human patients suffering from Pendred syndrome.
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas 66506, USA. wange@vet.ksu.edu
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Rajanikanth J
authors.initials: RJ
authors.lastname: Maganti
authors.forename: Erin M
authors.initials: EM
authors.lastname: Itza
authors.forename: Joel D
authors.initials: JD
authors.lastname: Sanneman
authors.forename: Donald G
authors.initials: DG
authors.lastname: Harbidge
authors.forename: Sara
authors.initials: S
authors.lastname: Billings
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Marcus
mesh_terms: D000042:Absorption; D000143:Acids / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003051:Cochlea / Q000378:metabolism* / Q000503:physiopathology; D003638:Deafness / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D004711:Endolymphatic Duct / Q000378:metabolism* / Q000473:pathology; D005849:Gerbillinae; D006042:Goiter / Q000150:complications; D006198:Hair Cells, Auditory; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009994:Osmolar Concentration; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency; D000076988:Sulfate Transporters; D013577:Syndrome; D000098854:Kcnj10 Channel
chemical_list: D000143:Acids; D027321:Anion Transport Proteins; D001639:Bicarbonates; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D002118:Calcium