The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells

Sound stimuli are converted into electrical signals via gating of mechano-electrical transducer (It'V ') channels in the hair cell stereociliary bundle. The molecular composition of the MT channel is still not fully established, although transmembrane channel like protein isoform I (TMCI) may be one component. We found that in outer hair cells of Beethoven mice containing a MI12K point mutation in TWA, MT channels had a similar unitary conductance to that of wild-type channels but a reduced selectivity for Ca2+. The CP-dependent adaptation that adjusts the operating range of the channel was also impaired in Beethoven mutants, with reduced shifts in the relationship between MT current and hair bundle displacement for adapting steps or after lowering extracellular Ca2+; these effects may be attributed to the channel's reduced Ca2+ permeability. Moreover, the density of stereociiiary CaATPase pumps for Ca2+ extrusion was decreased in the mutant. The results suggest that a major component of channel adaptation is regulated by changes in intracellular Cat Consistent with this idea, the adaptive shift in the current displacement relationship when hair bundles were bathed in endolymph-like Ca21 saline was usually abolished by raising the intracellular Ca2+ concentration.