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LRRC52 regulates BK channel function and localization in mouse cochlear inner hair cells

C. Lingle,P. L. Martinez-Espinosa,Aizhen Yang-Hood,Luis E. Boero,Shelby Payne,Dora Persic,Babak V-Ghaffari,Maolei Xiao,Yu Zhou,X. Xia,S. Pyott,M. Rutherford

Published 2019 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Hair cells of the cochlea transduce mechanical energy into electrical signals. Acoustic stimulation of mechanotransduction channels generates a graded receptor potential that elicits glutamate release from hair cells onto postsynaptic auditory nerve fibers. The amplitude and time course of the receptor potential is shaped by activation of Ca2+- and voltage-dependent K+ channels (BK channels). Hair cell BK channels are unusual in that, even in the absence of Ca2+, they are activated at more negative potentials than any other known BK channel. Here we show that a specific regulatory gamma subunit, LRRC52, is a key determinant in inner hair cells of the negative activation range of BK channels. Furthermore, the absence of LRRC52 disrupts BK channel clustering and localization. The perception of sound relies on sensory hair cells in the cochlea that convert the mechanical energy of sound into release of glutamate onto postsynaptic auditory nerve fibers. The hair cell receptor potential regulates the strength of synaptic transmission and is shaped by a variety of voltage-dependent conductances. Among these conductances, the Ca2+- and voltage-activated large conductance Ca2+-activated K+ channel (BK) current is prominent, and in mammalian inner hair cells (IHCs) displays unusual properties. First, BK currents activate at unprecedentedly negative membrane potentials (−60 mV) even in the absence of intracellular Ca2+ elevations. Second, BK channels are positioned in clusters away from the voltage-dependent Ca2+ channels that mediate glutamate release from IHCs. Here, we test the contributions of two recently identified leucine-rich-repeat–containing (LRRC) regulatory γ subunits, LRRC26 and LRRC52, to BK channel function and localization in mouse IHCs. Whereas BK currents and channel localization were unaltered in IHCs from Lrrc26 knockout (KO) mice, BK current activation was shifted more than +200 mV in IHCs from Lrrc52 KO mice. Furthermore, the absence of LRRC52 disrupted BK channel localization in the IHCs. Given that heterologous coexpression of LRRC52 with BK α subunits shifts BK current gating about −90 mV, to account for the profound change in BK activation range caused by removal of LRRC52, we suggest that additional factors may help define the IHC BK gating range. LRRC52, through stabilization of a macromolecular complex, may help retain some other components essential both for activation of BK currents at negative membrane potentials and for appropriate BK channel positioning.

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