Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4.
Hearing depends on a high K(+) concentration bathing the apical membranes of sensory hair cells. K(+) that has entered hair cells through apical mechanosensitive channels is transported to the stria vascularis for re-secretion into the scala media(). K(+) probably exits outer hair cells by KCNQ4 K(+) channels(), and is then transported by means of a gap junction system connecting supporting Deiters' cells and fibrocytes() back to the stria vascularis. We show here that mice lacking the K(+)/Cl(-) (K-Cl) co-transporter Kcc4 (coded for by Slc12a7) are deaf because their hair cells degenerate rapidly after the beginning of hearing. In the mature organ of Corti, Kcc4 is restricted to supporting cells of outer and inner hair cells. Our data suggest that Kcc4 is important for K(+) recycling() by siphoning K(+) ions after their exit from outer hair cells into supporting Deiters' cells, where K(+) enters the gap junction pathway. Similar to some human genetic syndromes(), deafness in Kcc4-deficient mice is associated with renal tubular acidosis. It probably results from an impairment of Cl(-) recycling across the basolateral membrane of acid-secreting alpha-intercalated cells of the distal nephron.
Boettger
Thomas
T
Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, 20246 Hamburg, Germany.
Hübner
Christian A
CA
Maier
Hannes
H
Rust
Marco B
MB
Beck
Franz X
FX
Jentsch
Thomas J
TJ
D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000473:pathology; D000818:Animals; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D003638:Deafness / Q000235:genetics* / Q000473:pathology; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D006320:Hearing Tests; D006801:Humans; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D011188:Potassium / Q000378:metabolism; D027981:Symporters / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000096922:K Cl- Cotransporters
D011188:Potassium; D027981:Symporters; C119651:SLC12A7 protein, human; D000096922:K Cl- Cotransporters; C492282:Slc12a7 protein, mouse