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1.A.82 The Hair Cell Mechanotransduction Channel (HCMC) Family

Mammalian hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not fully known. Xiong et al. (2012) showed that mechanotransduction is impaired in mice lacking the tetraspan membrane protein of hair cell stereocilia, TMHS, also known as lipoma HMGIC fusion partner-like 5, LHFPL5).

TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel (Xiong et al. 2012). Tmc1 and Tmc2 (TC#s 1.A.17.4.6 and 1.A.17.4.1, respectively) play important roles and are required for normal function of cochlear hair cells, possibly as Ca2+ channels or Ca2+ channel subunits (Kim and Fettiplace 2013).  Direct interactions between TMHS, PCDH15 and Tmc1 and Tmc2 have been demonstrated (Maeda et al. 2014; Beurg et al. 2015).

Mechanotransduction channels in hair cells are gated by tip links.  Zhao et al. 2014 showed that the transmembrane inner ear protein, TMIE (TC# 9.A.30), forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5 (TC# 1.A.82). Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis (Zhao et al. 2014).

References associated with 1.A.82 family:

Beurg, M., A.C. Goldring, and R. Fettiplace. (2015). The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells. J Gen Physiol 146: 233-243. 26324676
Beurg, M., W. Xiong, B. Zhao, U. Müller, and R. Fettiplace. (2015). Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc. Natl. Acad. Sci. USA 112: 1589-1594. 25550511
Fettiplace, R. (2016). Is TMC1 the Hair Cell Mechanotransducer Channel? Biophys. J. 111: 3-9. 27410728
Maeda, R., K.S. Kindt, W. Mo, C.P. Morgan, T. Erickson, H. Zhao, R. Clemens-Grisham, P.G. Barr-Gillespie, and T. Nicolson. (2014). Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc. Natl. Acad. Sci. USA 111: 12907-12912. 25114259
Ogun, O. and M. Zallocchi. (2014). Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly. J. Cell Biol. 207: 375-391. 25365995
Wu, Z., N. Grillet, B. Zhao, C. Cunningham, S. Harkins-Perry, B. Coste, S. Ranade, N. Zebarjadi, M. Beurg, R. Fettiplace, A. Patapoutian, and U. Müller. (2016). Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci. [Epub: Ahead of Print] 27893727
Xiong, W., N. Grillet, H.M. Elledge, T.F. Wagner, B. Zhao, K.R. Johnson, P. Kazmierczak, and U. Müller. (2012). TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells. Cell 151: 1283-1295. 23217710
Zhao, B., Z. Wu, N. Grillet, L. Yan, W. Xiong, S. Harkins-Perry, and U. Müller. (2014). TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron. 84: 954-967. 25467981