TRPV5, TRPV6, TRPM6, and TRPM7 do not contribute to hair-cell mechanotransduction

Abstract

The hair-cell mechanotransduction channel remains unidentified. We tested whether four transient receptor channel (TRP) family members, TRPV5, TRPV6, TRPM6, and TRPM7, participated in transduction. Using cysteine-substitution mouse knock-ins and methanethiosulfonate reagents selective for those alleles, we found that inhibition of TRPV5 or 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 could participate in transduction. Cochlear hair cell transduction was insensitive to shRNA knockdown of Trpm6 or Trpm7, however, and was not affected by manipulations of Mg 2+ , 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 TRPV5, TRPV6, TRPM6, and TRPM7 are unlikely to be the pore-forming subunit of the hair-cell transduction channel.

Molecular Structure of the Hair Cell Mechanoelectrical Transduction Complex

“…Many candidates have been examined, but almost all failed most of the criteria defining a bona fide MET channel. Some compelling candidates that have been ruled out are TRPN1/ NOMPC (Sidi et al 2003;Shin et al 2005), TRPV4/VR-OAC (Liedtke et al 2000), TRPA1 (Corey et al 2004;Kwan et al 2006), TRPV6, TRPM6, TRPM7 (Morgan et al 2017), HCN1 (Ramakrishnan et al 2009;Horwitz et al 2010), TRPML3 (Grimm et al 2007;Nagata et al 2008;van Aken et al 2008;Jors et al 2010), PKD1 (Steigelman et al 2011;Wu et al 2016), PKD2 (Fettiplace 2009;Wu et al 2016), TRPC3/TRPC6 (Quick et al 2012;Wu et al 2016), and TRPM1 (Gerka-Stuyt et al 2013;Wu et al 2016). However, recent studies based on the analysis of the function of genes linked to hearing loss have finally identified proteins that are integral components of the MET complex of hair cells and regulate its assembly and function.…”