Modulation of Rat Auditory Hair Cell Mechanotransduction Channel Resting Open Probability Implicates a Role for the Lipid Bilayer

Abstract

The auditory system is the most sensitive mechanosensory system known, able to detect movement down to atomic dimensions (Bialek. 1987. Annu. Rev. Biophys. Biophys. Chem. 16: 455-478). This sensitivity is at least partly attributed to the mechanisms associated with gating of hair cell mechanotransduction (MET) channels, where at rest approximately 50% of the channels are open, positioning the channels at the steepest part of their activation curve (Johnson et al. 2011. Neuron 70, 1143-1154). Previously, a calcium-regulated adaptation process was thought to control the resting open probability of MET channels (Farris, Wells, and Ricci. 2006. J. Neurosci. 26: 12526-12536). However, mammalian cochlear hair cell adaptation is not driven by calcium and low external calcium effects on resting open probability occur via an uncharacterized extracellular mechanism (Peng, Effertz, and Ricci. 2013. Neuron 80: 960-972). Upon further characterization of the extracellular mechanism, we find that large radii divalent ions act similarly to calcium intimating a nonspecific divalent ion mechanism. We show that hair cell depolarization also increases the resting open probability, and acts through a similar mechanism as the external calcium. Finally, we find that GsMTx4, a purported lipid-mediated stretch-activated channel modifier, blocks both the voltage and the low external calcium effects on resting open probability with only a minor decrease in adaptation. These results suggest a new, probably lipid-mediated, mechanism of calcium modulation of the hair cell MET channel independent of adaptation. Additionally, these results suggest that auditory mechanotransduction channel may have similar mechanisms to other mechanically-sensitive ion channels.This work was supported by RO1 DC0003896 to AJR, F32 DC010975 and K99 DC013299 to AWP, and NIDCD Core Grant P30-44992.