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After earning his B.A. in Chemistry at Reed College, Peter Gillespie received his Ph.D. in Pharmacology from the University of Washington in 1988. He was a postdoctoral fellow, first at the University of California, San Francisco until 1989, then at the University of Texas Southwestern Medical Center until 1993. In 1993, Gillespie went to Johns Hopkins University, where he rose to the rank of associate professor in the Department of Physiology. He was appointed as an associate professor in the Oregon Hearing Research Center, with a joint appointment at the Vollum Institute in 1999, and was promoted to professor in 2003. Gillespie has been director of the Neuroscience Graduate Program since 2002. Research InterestsThe internal ear’s hair cells allow the appreciation of sound and the maintenance of balance. A hair cell transduces auditory and vestibular stimuli into electrical responses by using its transduction apparatus, a molecular machine capable of detecting deflections of atomic dimensions. Residing in the hair bundle, this transduction apparatus consists of a transduction channel, a mechanically gated ion channel; a tip link, the extracellular filament that transmits force to the channel’s gate; and an adaptation motor, an ensemble that maintains an optimal tension in the tip link. Work carried out by the Gillespie laboratory has led to the identification of two out of three of these key elements. To identify the myosin responsible for adaptation, the Gillespie lab mutated myosin-1c to impart sensitivity to N6-modified ADP analogs. By introducing the mutated molecules into hair cells and showing that adaptation was inhibited by the ADP analog, they were able to conclude that myosin-1c mediates adaptation. Proving that myosin-1c is the adaptation motor has invigorated the search for its binding partners. One key partner is the phospholipid PIP2, which has a remarkable distribution in hair cells. The Gillespie laboratory contributed to the identification of cadherin 23 as the tip link. Immunocytochemistry demonstrated that cadherin 23 is present at tip link sites and at links between the tallest stereocilia and the kinocilium, which are immunologically related to tip links. Cadherin 23 expressed in tissue culture cells interacts with myosin-1c, suggesting a route to identification of proteins that couple myosin-1c to other members of the transduction apparatus. Other work has focused on the plasma membrane calcium pump. A plasma membrane Ca2+-ATPase is essential for auditory and vestibular function and may control Ca2+ entering during transduction, signal tip link loss, and locally elevate extracellular Ca2+ levels. The lab has identified the precise isozyme responsible for hair bundle Ca2+ regulation, PMCA2a, and has designed a new mutant-inhibitor approach to tease out its role in hair cell function. Future work will focus on identifying how the adaptation-motor myosin interacts with tip links, as well as determining the role of phospholipids in hair cell function. In addition, there is an ongoing effort to identify and characterize the transduction channel. Once elements of the transduction apparatus have been identified, the lab will study how they are assembled to make transduction so sensitive during development, turnover, and regeneration. Selected PublicationsHirono, M., Denis, C.S., Richardson, G.P., and Gillespie, P.G. (2004). Phosphatidylinositol-4,5-bisphosphate modulates transduction and adaptation in sensory hair cells. Neuron 44:309-320. Siemens, J, Lillo, C., Dumont, R.A., Reynolds, A., Williams, D.S., Gillespie, P.G., and Müller, U. (2004). Cadherin 23 is a component of the tip link in hair cell stereocilia. Nature 428:950-955. Cyr, J., Dumont, R., and Gillespie, P.G. (2002). Myosin-1c interacts with hair-cell receptors through calmodulin-binding IQ domains. J. Neurosci. 22:2487-2495. Holt, J. R, Gillespie, S.K.H., Provance, D.W., Shah, K., Shokat, K.M., Corey, D.P., Mercer, J.A., and Gillespie, P.G. (2002). A chemical-genetic strategy demonstrates myosin-1c participates in adaptation by hair cells. Cell 108:371-381. Dumont, R. A., Lins, U., Filoteo, A.G., Penniston, J., Kachar, B., and Gillespie, P.G. (2001). PMCA2a is the plasma-membrane Ca2+-ATPase of hair bundles. J. Neurosci. 21:5066-5078. Kachar, B., Parakkal, M., Kurc, M., Zhao, Y.-D., and Gillespie, P. G. (2000). Helical structure of hair-cell tip links revealed by freeze-etch microscopy. Proc. Natl. Acad. Sci. USA 97:13336-13341.
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