Reactome | MET channel transports cations from the extracellular region into the cytosol of stereocilia of cochlear outer hair cell

MET channel transports cations from the extracellular region into the cytosol of stereocilia of cochlear outer hair cell

Stable Identifier

R-MMU-9663360

Type

Reaction [transition]

Species

Mus musculus

Compartment

plasma membrane

ReviewStatus

5/5

General

SBML | | PDF

SVG | | PPTX | SBGN

MET channel transports cations from the extracellular region into the cytosol of stereocilia of cochlear outer hair cell

The mechanoelectrical transduction (MET) channels (also called mechanotransducer channels) located at the tips of stereocilia on the apical surface of outer hair cells (OHCs) are opened by mechanical force exerted on the channels by Cdh23:Pcdh15 tip links that traverse the tips of stereocilia (Siemens et al. 2004, Ahmed et al. 2006, Kazmierczak et al. 2007, Narui and Sotomayor 2018, Oroz et al. 2019). A Cdh23 dimer is connected to the cytoskeleton of a taller stereocilium via Ush1c (Harmonin), Ush1g (SANS), and Myo7a (MyoVIIa) (Boeda et al. 2002, Adato et al. 2005, Bahloul et al. 2010, Grati and Kachar 2011, Bahloul et al. 2017). By a calcium-dependent interaction, a Cdh23 dimer on a taller stereocilium is bound to a Pcdh15 dimer (Elledge et al. 2010, Schwander et al. 2009, Sotomayor et al. 2010) that is connected to a MET channel on a shorter stereocilium. The MET channel comprises at least Tmc1 and Tmc2 (Kawashima et al. 2011, Pan et al. 2013, Beurg et al. 2015, Kurima et al. 2015, Corns et al. 2016, Beurg et al. 2018, Pan et al. 2018, Beurg et al. 2019, Goldring et al. 2019), Tmie (Zhao et al. 2014), and the auxiliary subunits Cib2 (Michel et al. 2017, Wang et al. 2017) and Lhfpl5 (also called Tmhs), which interacts with Pcdh15 (Xiong et al. 2012, Geng et al. 2013, Beurg et al. 2015, Ge et al. 2018). In mice, Tmc2 expression is highest during the first week after birth and decreases in adulthood; Tmc1 expression is low in the first week after birth and increases in adulthood (Kawashima et al. 2011, Kurima et al. 2015). The MET channel may also contain additional, unidentified proteins (Beurg et al. 2014).
Deflection of the stereocilia by sound causes increased tension on Cdh23:Pcdh15, resulting in an increased probability of the open state of the MET channel (Beurg et al. 2006, Pan et al. 2013, Beurg et al. 2018, Pan et al. 2018). The MET channel is relatively non-specific for cations (inferred from rat homologs) and allows calcium ions (Kim and Fettiplace 2013, Pan et al. 2013, Beurg et al. 2015, Corns et al. 2016, Corns et al. 2017) and potassium ions to pass from the extracellular scala media to the cytosol of the OHC. Depolarization of the OHC results in shortening of the OHC due to a change in conformation of Slc26a5 (prestin) located in the membrane of the OHC. The composition of the cytoskeleton of OHCs differs from that of inner hair cells (IHCs): MPP1 (Mburu et al. 2006) and GSN (Mbruru et al. 2010, Olt et al. 2014) are present in OHCs but absent from IHCs.

Literature References

PubMed ID	Title	Journal	Year
25550511	Subunit determination of the conductance of hair-cell mechanotransducer channels Beurg, M, Xiong, W, Zhao, B, Fettiplace, R, Müller, U	Proc. Natl. Acad. Sci. U.S.A.	2015
26321635	TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia Millis, BA, Nakanishi, H, Choi, BY, Ebrahim, S, Monahan, K, Sengupta, P, Pan, B, Fujikawa, T, Cui, R, Holt, JR, Griffith, AJ, Kawashima, Y, Kachar, B, Sedlacek, M, Kurima, K	Cell Rep	2015
17805295	Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells Tokita, J, Sakaguchi, H, Kazmierczak, P, Milligan, RA, Wilson-Kubalek, EM, Kachar, B, Müller, U	Nature	2007
31633194	The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells Goldring, AC, Beurg, M, Fettiplace, R	J. Physiol. (Lond.)	2019
16829577	Whirlin complexes with p55 at the stereocilia tip during hair cell development Romero, R, Yonekawa, H, Kikkawa, Y, Brown, SD, Mburu, P, Townsend, S	Proc. Natl. Acad. Sci. U.S.A.	2006
29443515	Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15 Narui, Y, Sotomayor, M	Biochemistry	2018
31527607	Nanomechanics of tip-link cadherins Carrión-Vázquez, M, Oroz, J, Hervás, R, Fernández-Bravo, D, Valbuena, A, Galera-Prat, A	Sci Rep	2019
15590703	Interactions in the network of Usher syndrome type 1 proteins Petit, C, Adato, A, Alagramam, KN, El-Amraoui, A, Yonekawa, H, Kikkawa, Y, Wolfrum, U, Weil, D, Reiners, J, Michel, V	Hum. Mol. Genet.	2005
20661277	Gelsolin plays a role in the actin polymerization complex of hair cell stereocilia Parker, A, Kikkawa, Y, Brown, SD, Hilton, H, Mburu, P, Townsend, S, Romero, MR	PLoS ONE	2010
19270079	A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells Lelli, A, Kolatkar, A, Tokita, J, Xiong, W, Schwander, M, Wiltshire, T, Tarantino, L, Kuhn, P, Holt, JR, Kazmierczak, P, Kachar, B, Müller, U, Elledge, HM, Sczaniecka, A	Proc. Natl. Acad. Sci. U.S.A.	2009
20498078	Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members Kolatkar, A, Clark, P, Kazmierczak, P, Joseph, JS, Müller, U, Kuhn, P, Elledge, HM	Proc. Natl. Acad. Sci. U.S.A.	2010
29084757	CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival Petit, C, Lelli, A, Labbé, M, Dégardin, J, Bowl, MR, Bahloul, A, Aghaie, A, El-Amraoui, A, Azaiez, H, Cortese, M, Dupont, T, Brown, SD, Kahrizi, K, Booth, KT, Oficjalska-Pham, D, Patni, P, Avan, P, Smith, RJ, Emptoz, A, Najmabadi, H, Picaud, S, Michel, V	EMBO Mol Med	2017
20399731	Structural determinants of cadherin-23 function in hearing and deafness Gaudet, R, Weihofen, WA, Corey, DP, Sotomayor, M	Neuron	2010
31548403	A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells Beurg, M, Furness, DN, Fettiplace, R, Barlow, A	Proc. Natl. Acad. Sci. U.S.A.	2019
26758827	Tmc1 Point Mutation Affects Ca2+ Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells Corns, LF, Marcotti, W, Kros, CJ, Johnson, SL	J. Neurosci.	2016
26324676	The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells Goldring, AC, Beurg, M, Fettiplace, R	J. Gen. Physiol.	2015
21709241	Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction Grati, M, Kachar, B	Proc. Natl. Acad. Sci. U.S.A.	2011
25467981	TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells Wu, Z, Harkins-Perry, S, Xiong, W, Grillet, N, Yan, L, Zhao, B, Müller, U	Neuron	2014
23467356	Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells Furness, D, Chen, DH, Gaudet, R, Geng, R, Ball, G, Hardisty-Hughes, RE, Gerka-Stuyt, J, Parker, A, Gopal, SR, Alagramam, KN, Corey, DP, Brown, SD, Kinder, KJ, Sotomayor, M	J. Neurosci.	2013
29093662	TMC2 Modifies Permeation Properties of the Mechanoelectrical Transducer Channel in Early Postnatal Mouse Cochlear Outer Hair Cells Richardson, GP, Jeng, JY, Corns, LF, Marcotti, W, Kros, CJ	Front Mol Neurosci	2017
12485990	Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle Petit, C, Boëda, B, Houdusse, A, Blanchard, S, Goodyear, R, Bahloul, A, El-Amraoui, A, Wolfrum, U, Reiners, J, Fath, KR, Legrain, P, Daviet, L, Shorte, S, Richardson, G, Perfettini, I	EMBO J.	2002
23277480	Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel-like proteins Kim, KX, Fettiplace, R	J. Gen. Physiol.	2013
24475274	The actin-binding proteins eps8 and gelsolin have complementary roles in regulating the growth and stability of mechanosensory hair bundles of mammalian cochlear outer hair cells Kuhn, S, Bowl, M, Marcotti, W, Brown, SD, Mburu, P, Olt, J, Parker, A, Johnson, SL	PLoS ONE	2014
30070639	Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5 Elferich, J, Goehring, A, Gouaux, E, Schuck, P, Ge, J, Zhao, H	Elife	2018
15057245	Cadherin 23 is a component of the tip link in hair-cell stereocilia Dumont, RA, Williams, DS, Siemens, J, Reynolds, A, Müller, U, Gillespie, PG, Lillo, C	Nature	2004
28653419	Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery Petit, C, Baron, B, Hardelin, JP, Bahloul, A, El-Amraoui, A, Durand, D, Cordier, F, Nouaille, S, Pepermans, E, England, P, Wolff, N, Raynal, B	FEBS Lett.	2017
16807332	The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15 Frolenkov, GI, Goodyear, R, Wilcox, ER, Behra, M, Burgess, SM, Friedman, TB, Lagziel, A, Belyantseva, IA, Richardson, GP, Griffith, AJ, Legan, PK, Ahmed, ZM, Lilley, KS, Riazuddin, S, Riazuddin, S	J. Neurosci.	2006
20639393	Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids Petit, C, Hoos, S, Houdusse, A, Hardelin, JP, Bahloul, A, Michel, V, Nouaille, S, England, P	Hum. Mol. Genet.	2010
30138589	TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells György, B, Nist-Lund, C, Pan, B, Akyuz, N, Holt, JR, Limapichat, W, Liu, XP, Wimalasena, LN, Corey, DP, Walujkar, S, Asai, Y, Derfler, BH, Sotomayor, M, Kurima, K	Neuron	2018
29255404	Loss of CIB2 Causes Profound Hearing Loss and Abolishes Mechanoelectrical Transduction in Mice Yao, X, Wang, Y, Chai, R, Li, W, Xiong, W, Tang, M, Du, H, Li, J, Xu, Z	Front Mol Neurosci	2017
24981230	Conductance and block of hair-cell mechanotransducer channels in transmembrane channel-like protein mutants Beurg, M, Kim, KX, Fettiplace, R	J. Gen. Physiol.	2014
23217710	TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells Johnson, KR, Kazmierczak, P, Xiong, W, Grillet, N, Zhao, B, Müller, U, Elledge, HM, Wagner, TF	Cell	2012
22105175	Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes Lelli, A, Holt, JR, Wu, DK, Griffith, AJ, Makishima, T, Kawashima, Y, Labay, V, Géléoc, GS, Asai, Y, Della Santina, CC, Kurima, K	J. Clin. Invest.	2011
23871232	TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear Holt, JR, Griffith, AJ, Kawashima, Y, Ishikawa, K, Horwitz, GC, Pan, B, Géléoc, GS, Asai, Y, Kurima, K	Neuron	2013