title: TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells.
abstract: 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 known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. 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. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.
authors.affiliation: The Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grillet
authors.forename: Heather M
authors.initials: HM
authors.lastname: Elledge
authors.forename: Thomas F J
authors.initials: TF
authors.lastname: Wagner
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Piotr
authors.initials: P
authors.lastname: Kazmierczak
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006309:Hearing; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D011498:Protein Precursors / Q000378:metabolism; D059547:Stereocilia / Q000378:metabolism
chemical_list: C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C000624587:LHFPL5 protein, mouse; D008565:Membrane Proteins; D011498:Protein Precursors