Two classes of outer hair cells along the tonotopic axis of the cochlea.
The molecular basis of high versus low frequency hearing loss and the differences in the sensitivity of outer hair cells depending on their cochlear localization are currently not understood. Here we demonstrate the existence of two different outer hair cell phenotypes along the cochlear axis. Outer hair cells in low frequency regions exhibit early sensitivity for loss of Ca(v)1.3 (alpha1 subunit 1.3 forming the class D L-type voltage-gated Ca(2+) channel), while high frequency regions display a progressive susceptibility for loss of the Ca(2+)-activated large conductance K(+) (BK) channel. Despite deafness, young Ca(v)1.3-deficient mice displayed distortion-product otoacoustic emissions (DPOAEs), indicating functional outer hair cells in the higher frequency range of the cochlea. Considering that DPOAEs are also found in the human deafness syndrome DFNB9 caused by mutations in the synaptic vesicle protein otoferlin, we tested the expression of otoferlin in outer hair cells. Surprisingly, otoferlin showed a distinct tonotopic expression pattern at both the mRNA and protein level. Otoferlin-expressing, Ca(v)1.3 deletion-sensitive outer hair cells in the low frequency range could be clearly separated from otoferlin-negative, BK deletion-sensitive outer hair cells in the high frequency range. In addition, BK deletion led to a higher noise vulnerability in low frequency regions, which are normally unaffected by the BK deletion alone, suggesting that BK currents are involved in survival mechanisms of outer hair cells under noise conditions. Our findings propose new mechanisms and candidate genes for explaining high and low frequency hearing loss.
Engel
J
J
University of Tübingen, Institute of Physiology II and Department of Otolaryngology, THRC, Gmelinstrasse 5, 72076 Tübingen, Germany.
Braig
C
C
Rüttiger
L
L
Kuhn
S
S
Zimmermann
U
U
Blin
N
N
Sausbier
M
M
Kalbacher
H
H
Münkner
S
S
Rohbock
K
K
Ruth
P
P
Winter
H
H
Knipper
M
M
D000161:Acoustic Stimulation / Q000379:methods; D000429:Alcohol Oxidoreductases; D000818:Animals; D000831:Animals, Newborn; D001309:Auditory Threshold / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000172:deficiency; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000166:cytology* / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D018072:Hair Cells, Auditory, Outer / Q000166:cytology* / Q000502:physiology*; D006319:Hearing Loss, Sensorineural / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000172:deficiency / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017084:Otoacoustic Emissions, Spontaneous / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C516233:otoferlin protein, mouse; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse