Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BKbeta1-subunit leads to progressive hearing loss.
The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming alpha-subunit coexpressed with the auxiliary beta1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha-/-) and beta1-subunit (BKbeta1-/-) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta1-/- mice. During the first 4 postnatal weeks also, BKalpha-/- mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKalpha-/- mice only from approximately 8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations.
Rüttiger
Lukas
L
Department of Otorhinolaryngology, Tübingen Hearing Research Center, Molecular Neurobiology, University of Tübingen, Elfriede-Aulhorn-Strasse 5, D-72076 Tübingen, Germany.
Sausbier
Matthias
M
Zimmermann
Ulrike
U
Winter
Harald
H
Braig
Claudia
C
Engel
Jutta
J
Knirsch
Martina
M
Arntz
Claudia
C
Langer
Patricia
P
Hirt
Bernhard
B
Müller
Marcus
M
Köpschall
Iris
I
Pfister
Markus
M
Münkner
Stefan
S
Rohbock
Karin
K
Pfaff
Imke
I
Rüsch
Alfons
A
Ruth
Peter
P
Knipper
Marlies
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003051:Cochlea / Q000378:metabolism; D017353:Gene Deletion; D018072:Hair Cells, Auditory, Outer / Q000002:abnormalities; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051379:Mice; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism
C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D002118:Calcium