Beurg Maryline, Goldring Adam C, Fettiplace Robert
Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706.
Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706
J Gen Physiol. 2015 Sep;146(3):233-43. doi: 10.1085/jgp.201511458.
Sound stimuli are converted into electrical signals via gating of mechano-electrical transducer (MT) 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 1 (TMC1) may be one component. We found that in outer hair cells of Beethoven mice containing a M412K point mutation in TMC1, MT channels had a similar unitary conductance to that of wild-type channels but a reduced selectivity for Ca(2+). The Ca(2+)-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 Ca(2+); these effects may be attributed to the channel's reduced Ca(2+) permeability. Moreover, the density of stereociliary CaATPase pumps for Ca(2+) extrusion was decreased in the mutant. The results suggest that a major component of channel adaptation is regulated by changes in intracellular Ca(2+). Consistent with this idea, the adaptive shift in the current-displacement relationship when hair bundles were bathed in endolymph-like Ca(2+) saline was usually abolished by raising the intracellular Ca(2+) concentration.
声音刺激通过毛细胞静纤毛束中的机械电转换（MT）通道门控被转换为电信号。尽管跨膜通道样蛋白异构体1（TMC1）可能是其中一个组成部分，但MT通道的分子组成仍未完全确定。我们发现，在TMC1中含有M412K点突变的贝多芬小鼠的外毛细胞中，MT通道的单位电导与野生型通道相似，但对Ca(2+)的选择性降低。在贝多芬突变体中，调节通道工作范围的Ca(2+)依赖性适应也受损，对于适应步骤或降低细胞外Ca(2+)后，MT电流与毛束位移之间关系的变化减小；这些效应可能归因于通道Ca(2+)通透性的降低。此外，突变体中用于Ca(2+)外排的静纤毛CaATPase泵的密度降低。结果表明，通道适应的一个主要成分受细胞内Ca(2+)变化的调节。与此观点一致，当毛束浸泡在内淋巴样Ca(2+)盐溶液中时，电流-位移关系的适应性变化通常会因提高细胞内Ca(2+)浓度而消除。
