title: TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells.
abstract: Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. 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.
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grillet
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Linxuan
authors.initials: L
authors.lastname: Yan
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Harkins-Perry
authors.affiliation: Dorris Neuroscience Center, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: umueller@scripps.edu.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D057809:HEK293 Cells; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000235:genetics*; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D020409:Molecular Motor Proteins / Q000235:genetics; D009924:Organ Culture Techniques; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C515721:LHFPL5 protein, human; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; C498720:Pres protein, mouse; D011498:Protein Precursors; C514628:TMC1 protein, mouse; C575755:TMC2 protein, mouse; C530887:Tmie protein, mouse; D013629:Tamoxifen; C016601:afimoxifene