Personal History:My doctorate in biophysics was taken at U.C.L.A. in the laboratory of Dr. T.H. Bullock. I then did postdoctoral training at Columbia University, College of Physicians and Surgeons in the laboratory of Dr. H. Grundfest before coming to the University of Maryland in 1965. I had the opportunity to work with Professor T.I. Shaw at the University of London, supported by a N.A.T.O. Senior Fellowship in Science. I have also worked at Cambridge University and at the I. Physiologisches Institut, Universitat des Saarlandes, supported by a Fullbright Senior Professorship. I am a fellow of the American Association For the Advancement of Science.
Research Interests:Electrical signals generated by the membranes of living cells constitute one of the most critically import of all biological phenomena. They trigger muscle contraction, underlie the rhythmic contractions of the heart and transmit information about the outside world to the brain. In the brain, incoming signals are decoded, analyzed and integrated with other information. New signals are generated, again encoding information, and then transmitted to other sites. Electrical signals are central for the brain’s ability to process information, and ultimately, then, for behavior. My laboratory studies the fundamental physical processes by which membranes generate electrical signals with the goal of elucidating the basic biophysical mechanisms underlying the information processing properties of excitable cells.
Membrane electrical activity is mediated by certain classes of integral membrane proteins which form ionic channels through the membrane. To understand the operation of these ionic channels one must understand two processes: voltage gating and ion permeation. Gating is the process by which channels change their availability for ion passage as a response to channels in the membrane electrical field. Permeation refers to the physical mechanisms by which ions transverse the membrane and the origin of ion selectivity. My laboratory studies both of these basic process. Techniques utilized include recording of membrane currents under controlled, voltage clamped conditions. We study both the whole-cell, macroscopic ionic current and the gating current. Gating current is a very small, very rapid non-linear component of the membrane capacitative current which is the electrical sign of the actual operation of the channel gating machinery. In addition, studies are carried out on the currents flowing through single ion channels, using the patch clamp. My laboratory also has a strong interest in theoretical studies.
Some completed studies include the first detailed analysis of sodium channel inactivation from closed states, utilizing single channel recording and a theoretical analysis of channel gating kinetics. Theoretical analysis showed that all closed states directly inactivate and do so with about the same closed to inactivated rate constant for each closed state. Experimental findings established that there is a range of moderately depolarized potentials for which nearly all the inactivation is from closed states. This result has implications for the information processing properties of nerve cells. Owing to closed state inactivation, low level synaptic depolarizations can completely inactivate the action potential initiating locus of a neuron without the accompanying generation of an action potential.
Other completed work, in collaboration with Dr. C. William Balke, includes the identification of a new sodium current component in ventricular cells. This new current component activates over a more negative range of potentials than does the classical cardiac sodium current and so will act to amplify the depoloarizaion delivered by the Purkinje fibers and serve, then, as the immediate trigger for the generation of the cardiac action potential. It constitutes a previously unrecognized new step in the cycle of normal cardiac electrical activity, and provides a new basis for the understanding of clinical cardiac arrhythmias and their control.