TRPV6, TRPM6 and TRPM7 Do Not Contribute to Hair-Cell Mechanotransduction

Abstract

Hair cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-cell mechanotransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on transduction in mouse cochlear hair cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic cells, which suggested they might be part of the transduction complex. Cochlear hair cell transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in transduction, we showed that deletion of either or both of their genes selectively in hair cells had no effect on auditory function. We suggest that TRPV6, TRPM6 and TRPM7 are unlikely to be the pore-forming subunit of the hair-cell transduction channel.

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

“…Interestingly, PCDH15 seems to interact promiscuously with multiple transmembrane proteins, including TMCs, various TRP channels, and TMHS (128)(129)(130)(131). The most compelling data on these interactions comes from the recent structural and biophysical characterization of the PCDH15 MAD12-TMHS complex (49).…”

The Cation Channel TMEM63B Is an Osmosensor Required for Hearing

“…Continuous oscillation and depolarization pose severe challenges of shape changing and swelling on OHCs, which are countered by Ca 2+ -dependent RVD process (Dulon and Schacht, 1992;Surin et al, 2000); however, the cation channels mediating OHC RVD remain unknown. Genetic deletion of TRP channels in the auditory systems led to little hearing defects (Morgan et al, 2018;Sexton et al, 2016;Wu et al, 2016), suggesting that TRP channels unlikely serve as the osmosensitive NSCCs in OHCs.…”

In Silico Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models

“…Several potential channel candidates have been proposed throughout the past two decades, including members of the TRP, HCN, ENaC, and ASIC families of proteins [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] . Despite the initial promise of each of these candidates, they all have been dismissed as none met all criteria listed above.…”