1.A.17.4.6
Transmembrane channel-like protein-1, Tmc1. Also called Transmembrane cochlear-expressed protein-1, Beethoven protein and deafness protein.  Required for normal function of cochlear hair cells, possibly as a Na⁺/K⁺/Ca²⁺ channel (Kim and Fettiplace 2013).  TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014).  Channel activity has been demonstrated for the C. elegans orthologue, and the mouse Tmc1.  The C. elegans Tmc1 is probably a Na⁺-activated Na⁺-selective mechanosensor. The C. elegans Tmc2 may be a Na⁺/K⁺ channel.  The mouse Tmc1 is functional and replaces Tmc2 when expressed in C. elegans (WR Schafer, personal communication).  Ca²⁺ currents are blocked by the peptide toxin GsMTx-4 (Beurg et al. 2014).  Tmc1 and Tmc2, expressed in cochlear and vestibular hair cells, are required for hair cell mechanoelectric transduction (Nakanishi et al. 2014); mutations disrupt mechanoelectric transduction and are a cause of autosomal dominant and recessive forms of nonsyndromic hearing loss (Gao et al. 2015).  Using the mutant mouse model (Tmc1; Beethoven) for progressive hearing loss in humans (DFNA36) this mutation has been shown to affect the MET channel pore, reducing its Ca²⁺ permeability and its affinity for the permeant blocker, dihydrostreptomycin (Corns et al. 2016).  Evidence for TMC1 being the hair cell mechanosensitive channel has been evaluated (Fettiplace 2016).  The human orthologue (UniProt acc # Q8TDI8) is 96% identical. Mouse LHFPL5 ((HMGIC fusion partner-like protein 5) co-expresses with TMC1 in auditory hair cells (Li et al. 2019). A region within the N-terminus of mouse TMC1 (residues 138 - 168) precludes trafficking from an intracellular location to the plasma membrane (Soler et al. 2019). TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of mouse auditory hair cells (Liu et al. 2019). VRISPER/Cas has been used to correct defects that result in hereditary hearing loss (Farooq et al. 2020). Repair of Tmc1 via genetic engineering in vivo restored inner hair cell sensory transduction and hair cell morphology and transiently rescued low-frequency hearing (Yeh et al. 2020). TMC1 forms a mechano-electrical transduction channel, which transduces mechanical stimuli into electrical signals at the top of stereocilia of hair cells in the inner ear. Yamaguchi et al. 2023 found that the cytosolic N-terminal region of heterologously-expressed mouse TMC1 (mTMC1) was localized in nuclei of a small population of the transfected HEK293 cells. This raised the possibility that the N-terminal region of heterologously-expressed mTMC1 was cleaved and transported into the nucleus (Yamaguchi et al. 2023).