title: The role of transmembrane channel-like proteins in the operation of hair cell mechanotransducer channels.
abstract: Sound stimuli elicit movement of the stereocilia that make up the hair bundle of cochlear hair cells, putting tension on the tip links connecting the stereocilia and thereby opening mechanotransducer (MT) channels. Tmc1 and Tmc2, two members of the transmembrane channel-like family, are necessary for mechanotransduction. To assess their precise role, we recorded MT currents elicited by hair bundle deflections in mice with null mutations of Tmc1, Tmc2, or both. During the first postnatal week, we observed a normal MT current in hair cells lacking Tmc1 or Tmc2; however, in the absence of both isoforms, we recorded a large MT current that was phase-shifted 180°, being evoked by displacements of the hair bundle away from its tallest edge rather than toward it as in wild-type hair cells. The anomalous MT current in hair cells lacking Tmc1 and Tmc2 was blocked by FM1-43, dihydrostreptomycin, and extracellular Ca(2+) at concentrations similar to those that blocked wild type. MT channels in the double knockouts carried Ca(2+) with a lower permeability than wild-type or single mutants. The MT current in double knockouts persisted during exposure to submicromolar Ca(2+), even though this treatment destroyed the tip links. We conclude that the Tmc isoforms do not themselves constitute the MT channel but are essential for targeting and interaction with the tip link. Changes in the MT conductance and Ca(2+) permeability observed in the absence of Tmc1 mutants may stem from loss of interaction with protein partners in the transduction complex.
authors.affiliation: Department of Neuroscience, University of Wisconsin Medical School, Madison, WI 53706.
authors.forename: Kyunghee X
authors.initials: KX
authors.lastname: Kim
authors.forename: Maryline
authors.initials: M
authors.lastname: Beurg
authors.forename: Carole M
authors.initials: CM
authors.lastname: Hackney
authors.forename: David N
authors.initials: DN
authors.lastname: Furness
authors.forename: Shanthini
authors.initials: S
authors.lastname: Mahendrasingam
authors.forename: Robert
authors.initials: R
authors.lastname: Fettiplace
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D021461:Animals, Outbred Strains; D003638:Deafness / Q000235:genetics / Q000503:physiopathology*; D018072:Hair Cells, Auditory, Outer / Q000502:physiology* / Q000648:ultrastructure; D008465:Mechanoreceptors / Q000502:physiology / Q000648:ultrastructure; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D008954:Models, Biological; D009925:Organ of Corti / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C514628:TMC1 protein, mouse; C575755:TMC2 protein, mouse