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After earning his B.A. in Biophysics at the University of California at Berkeley, Edwin McCleskey received his Ph.D. in Physiology from the University of Washington in 1983. He was a research associate at the University of Washington until 1984, then spent the next two years as a research fellow in the Department of Physiology at Yale University. In 1987, McCleskey went to Washington University, where he rose to the rank of associate professor in the Department of Cell Biology and Physiology. He has been at the Vollum Institute since 1993 and is currently a senior scientist. McCleskey is co-director of the summer Neurobiology course at the Marine Biological Laboratory in Woods Hole, Massachusetts. Research InterestsWhat are the molecular mechanisms that trigger pain? The McCleskey lab focuses on ischemic pain, the pain that occurs in muscle, bone, and some visceral organs when they get insufficient oxygen for their needs. The most obvious examples of such pain accompany blockade of blood vessels. These include the pain due to coronary vascular disease (angina), peripheral vascular disease (intermittent claudication), and sickle cell anemia. When an organ gets insufficient oxygen, it generates lactic acid, which then accumulates in the extracellular space. The McCleskey lab has found that certain sensory neurons that innervate muscle respond electrically to acid because they express a high level of an ion channel called ASIC3, acid-sensing ion channel #3. This channel is the most sensitive biological pH detector. Moreover, they find that the channel can integrate multiple signals that occur during ischemia, thereby explaining why acidity caused by ischemia hurts whereas acidity caused by respiratory or metabolic problems does not. Specifically, the presence of extracellular lactate or extracellular ATP both increase the sensitivity of the channel to decreasing pH. Present work in the lab aims to describe basic properties of acid-sensing channels, to describe the molecular basis of modulation of pH sensitivity by lactate and ATP, and to devise ways to critically test the role of ASIC3 in pain. Most experiments use electrophysiology on individual cells. Selected PublicationsImmke, D.C. and McCleskey, E.W. (2003) Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 37:75-84. Immke, D.C. and McCleskey, E.W. (2001) Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nature Neurosci. 4:869-870. Sutherland, S.P., Benson, C.J., Adelman, J.P., and McCleskey, E.W. (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc. Natl. Acad. Sci. USA 98:711-716. Benson, C.J., Eckert, S.P., and McCleskey, E.W. (1999) Acid-evoked currents in cardiac sensory neurons: a possible mediator of myocardial ischemic sensation. Circ. Res. 84:921-928.
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