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Review
. 2016 Jul 12;111(1):3-9.
doi: 10.1016/j.bpj.2016.05.032.

Is TMC1 the Hair Cell Mechanotransducer Channel?

Robert Fettiplace  1
Affiliations
Review

Is TMC1 the Hair Cell Mechanotransducer Channel?

Robert Fettiplace. Biophys J. .

Abstract

Transmembrane channel-like protein isoform-1 (TMC1) has emerged over the past five years as a prime contender for the mechano-electrical transducer (MET) channel in hair cells of the inner ear. TMC1 is thought to have a six-transmembrane domain structure reminiscent of some other ion-channel subunits, and is targeted to the tips of the stereocilia in the sensory hair bundle, where the MET channel is located. Moreover, there are TMC1 mutations linked to human deafness causing loss of conventional MET currents, hair cell degeneration, and deafness in mice. Finally, mutations of Tmc1 can alter the conductance and Ca(2+) selectivity of the MET channels. For several reasons though, it is unclear that TMC1 is indeed the MET channel pore: 1) in other animals or tissues, mutations of TMC family members do not directly affect cellular mechanosensitivity; 2) there are residual manifestations of mechanosensitivity in hair cells of mouse Tmc1:Tmc2 double knockouts; 3) there is so far no evidence that expression of mammalian Tmc1 generates a mechanically sensitive ion channel in the plasma membrane when expressed in heterologous cells; and 4) there are other proteins, such as TMIE and LHFPL5, which behave similarly to TMC1, their mutation also leading to loss of MET current and deafness. This review will present these disparate lines of evidence and describes recent work that addresses the role of TMC1.

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Figures

Figure 1
Figure 1
The hair cell mechano-transduction apparatus. (A) Scanning electron micrograph of the V-shaped hair bundle of an OHC depicts three rows of stereocilia stepping in height across the bundle from 2 to 4 μm (4). (B) Some key molecular components of the transduction apparatus associated with the tip link through which force is applied to the MET channel. Tip links comprise homodimers of cadherin 23 (CDH23) at the upper end and protocadherin 15 (PCDH15) at the lower end. CDH23 is anchored to the stereociliary actin cytoskeleton by the Usher protein complex Myo7a, SANS, and harmonin-b (56). PCDH15 interacts with the MET channel via putative channel components LHFPL5 (50), TMIE (51), and TMC1 (53, 54). The MET channel may be connected to the actin cytoskeleton by Usher proteins whirlin and CIB2 (57) and Myo15a.
Figure 2
Figure 2
Structure of TMC1. (A) Putative transmembrane configuration based on tags and hydropathy plots indicate six transmembrane domains (S1 to S6), with intracellular N- and C termini, and a long intracellular loop between domains S4 and S5 (34). Point mutations causing progressive deafness in mice including Beethoven are denoted by red circles (20), and the hatched segment indicates amino acids 463–519 deleted in Tmc1 deafness (13), with numbering of residues referring to the mouse sequence. Point mutations causing deafness in humans are indicated by pink circles (16, 58, 59, 60), with residue numbering referring to the human sequence, which differs by a few residues from mouse; only those mutations causing amino-acid substitutions rather than truncations are noted. The mutated residues in the transmembrane domains are S1, G197, and N199; S2, P274, and Y277; S3 and V372; S4, G444, and R445; S5 and M654. The putative intracellular loop between S4 and S5 also includes two other potential transmembrane domains shown in blue (34). (B) Alternative structure is shown that incorporates the two additional transmembrane regions with connecting section forming a reentrant loop and pore that will include mutation sites W554 and D569. N-terminus shortened to save space. (C) A subunit of the dimeric ZnT-1 zinc transporter is shown that displays six transmembrane domains like some ion channels; the transporting region is built from S2 and S5, which are adjacent in the three-dimensional structure, with each containing crucial histidine and aspartate residues (49).
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