COLUMBIA UNIVERSITY • DEPARTMENT OF
Physiology and Cellular Biophysics

CURRENT RESEARCH

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Understanding the function of molecular receptors has been my guiding interest and the central mission of the Center. Receptors function in three steps: signal recognition, transduction, and transmission. This is exemplified by the nicotinic acetylcholine receptors, on which I worked for forty years. These receptors bind acetylcholine, transduce this binding into the opening of a pore, and conduct cations causing a depolarization of the synaptic membrane. We identified the overall receptor structure and, within this, the specific sites and substructures at the front-line of these functional steps. More recently, this approach was applied to the BK channel, a voltage- and calcium-ion-activated channel, widely expressed and responsible for membrane hyperpolarization.

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Also recently, I began to consider cellular functions that depend on circuits of signaling components. In these cases, in addition to individual molecular structures, cellular structures and the distribution of the molecular components in these structures determine the nature of the signaling that underlies the cellular function. Crucial to the specificity and effectiveness of the signaling are microdomains, which both channel and amplify the signals. My approach to understanding such systems is to represent all steps as kinetic equations and to solve the resulting equations in time and space. To the extent that experimental data exist, the equations are fit to these data. Such a model is a mathematical summary of the known properties of the components and of the target cellular function. It is also kinetically plausible and consistent with thermodynamics. Notwithstanding, such a model is a hypothetical outline of how the cell might function, always wanting experimental tests and refinement.