Description:

Speaker: Robert Fettiplace, PhD, Professor, Department of Neuroscience, University of Wisconsin - Madison

Talk title: Evidence on the Molecular Composition of the Hair-cell Transduction Channel Complex

Cochlear hair cells detect sound vibrations by displacements of the stereociliary bundle, which tensions tip links and opens mechanotransducer (MT) channels in the stereociliary membrane. The molecular structure of the MT channel has been sought for more than 20 years and is still not firmly identified but recent evidence suggests that TMC1, an isoform of the transmembrane channel like family, is a central component. Consistent with this idea, more than 30 mutations of TMC1 cause either profound or progressive deafness in humans and mice. The role of TMC1 will be addressed by measuring unitary conductance and ion permeability in MT channels of a variety of mouse mutants. An important finding is that, in Tmc1/Tmc2 double knockouts, normal MT currents are absent, but mechanically sensitive currents can still be evoked by negative displacements of the stereociliary bundle. These, referred to as reversed stimulus-polarity currents, have many properties similar to MT currents in wild-type; however, severing the tip links by treatment with BAPTA does not abolish the reversed stimulus-polarity currents as it would normal MT currents. We suggest that the reversed stimulus-polarity currents flow though nascent MT channels that have been newly exported to the top of the hair cell, where they lack accessory subunits or attachment to extracellular links. In the absence of TMC1 and TMC2, MT channels still exist but are not connected to the tip link. We further propose that TMC1 is not the channel pore but may, along with other proteins such as TMHS, constitute part of an external vestibule influencing channel conductance and permeability. If this suggestion is correct, the molecular identity of the pore-forming subunit is still unknown.

Sponsored by: The Roxelyn and Richard Pepper Department of Communication Sciences and Disorders