TMC Function in Hair Cell Mechanotransduction

Abstract

Sensory hair cells of the mammalian inner ear convert sound stimuli and head movements into electrical signals that are transmitted to the brain. The molecules and mechanisms of sensory transduction in inner ear hair cells have been the focus of considerable interest and investigation. Recently, we identified Transmembrane channel-like proteins 1 and 2 (TMC1 and TMC2) as components of the mechanosensitive ion channels in hair cells. The data suggest that TMC1 or TMC2 are required for hair cell transduction and that expression of either one is sufficient to retain mechanosensitivity. Although these molecules are somewhat redundant in their function, there are clear differences in the biophysical properties of mechanotransduction in hair cells that express only TMC1 or only TMC2. The biophysical differences include differences in the rate and extent of adaptation, differences in calcium permeability and differences in single-channel conductance. Wild-type hair cells that express both TMC1 and TMC2 have a broad range of single-channel conductances, raising the possibility that the proteins may interact to form channels with a range of biophysical properties. Both dominant and recessive mutations in Tmc1 cause deafness in mice and humans. To further characterize the contributions of TMC1 to hair cell function we examined hair cells of mice that carried a dominant point mutation in Tmc1 known as Beethoven (Bth). The Bth mutation is methionine to lysine substitution at amino acid position 412. We find that the Bth point mutation is not a dominant-negative, or loss-of-function mutation, but alters several biophysical properties of hair cell transduction. Relative to cells that express wild-type Tmc1, cells that express the Bth mutation have smaller single-channel conductance, larger calcium block, reduced calcium permeability and slower adaptation. These data provide strong evidence that implicate TMC1 as a component of the hair cell mechanotransduction channel.