David Corey, Ph.D.

 

Professor of Neurobiology

Harvard Medical School
Department of Neurobiology
Goldenson Building, Room 443
220 Longwood Avenue
Boston, MA 2115
Tel: 617-432-2506
Fax: 617-432-2508
Email: dcorey@hms.harvard.edu
Visit my lab page here.




We are interested in the gating of mechanically sensitive ion channels, which open in response to force on the channel proteins. We study these channels primarily in vertebrate hair cells -- the receptor cells of the inner ear, which are sensitive to sounds or accelerations. Hair cells are epithelial cells, with a bundle of stereocilia rising from their apical surfaces. Mechanical deflection of the bundles changes the tension in fine "tip links" that stretch between the stereocilia; these filaments are thought to pull directly on the mechanically-gated transduction channels to regulate their opening.

Tip links are made of two unusual cadherins with long extracellular domains--cadherin 23 and protocadherin 15—whose N-termini join to complete the link. We are interested in the tip link’s biophysical properties and how the two cadherins join. We have determined the crystal structure of the cadherin-23 and protocadherin N-termini bound to each other, and have used steered molecular dynamics to determine their elastic properties and unbinding force. The crystal structures and molecular dynamics together have helped explain how deafness-producing mutations in the tip link disrupt its structure. These simulations are being confirmed in vitro by pulling apart the bound complexes with laser tweezer forces.

To understand the mechanics of hair cell transduction, we have characterized the movement of stereocilia bundle with high-resolution light microscopy and strobe illumination. Stereocilia do not bend, but pivot at their bases, and they remain touching within 10 nm even as they slide past one another by hundreds of nanometers. This “sliding adhesion” confers independent gating on transduction channels.

Transduction channels open with a mechanical stimulus, but then adapt with a timecourse of milliseconds. One phase of adaptation was shown to be mediated by a motor complex of myosin-1c molecules relaxing tension on the channels, but a faster phase apparently results from Ca2+ that enters through the channels immediately binding to close them. We are characterizing the site of Ca2+ action by photolytically releasing Ca2+ inside stereocilia and measuring the nanometer movements that correspond to channel closing. Ca2+ imaging of single stereocilia reveals the site of ion channels within the stereocilia bundle, and whether it changes with development.

Finally, the force-gated ion channel that is pulled open by tip-link tension may be composed of TMC1 and TMC2. We are exploring the involvement of these two proteins and their binding partners in mechanosensation.


For a complete listing of publications click here.



Last Update: 11/7/2013