Cholinergic Inhibition of Hair Cells

KATZ E; ELGOYHEN AB; FUCHS PA

Auditory and Vestibular efferents

Springer

Lugar: New York; Año: 2011; p. 103 - 133

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US; mso-fareast-language:EN-US;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> The results described in this chapter support the hypothesis that cholinergic inhibition of cochlear hair cells is mediated by the a9a10-nAChR that allows Ca2+ into the cell and the subsequent activation of the calcium-dependent SK2 potassium channel. From the 1970s to 1990s, scientists contributed data supporting the notion of this ?two-channel? inhibitory mechanism. However, it was not until the cloning of the a9 subunit in 1994 that allowed its inclusion within the nicotinic family of cholinergic receptors. Then the cloning of the a10 subunit together with the biophysical and pharmacological characterization of the recombinant a9a10 nAChR showed that this heteromeric receptor resembled more closely the native receptor. The introduction of the cochlear coil preparation then fostered both the biophysical and pharmacological studies on the native nAChR and also allowed the direct stimulation of the efferent fibers to study the characteristics of transmitter release. These studies led to the conclusion that feedback from the central nervous system will only have an effect when it is strongly driven, preventing spontaneous activity from inadvertently altering cochlear function. Finally, the genetic manipulation of the molecules involved in the cholinergic inhibition of hair cells confirmed that the a9 and a10 nAChR subunits are fundamental components of the native receptor. Both the a9 and a10 knockout mice fail to show suppression of cochlear responses during efferent fiber activation, demonstrating the key role the a9a10 nAChRs play in mediating the effects of the OC system. In addition, the complete lack of cholinergic sensitivity of hair cells from SK2 knockout mice strongly suggests that this molecule has a central role and that it is necessary for the assembly, targeting and/or insertion of the nAChR into the membrane.