Ionic channels control nerve impulse conduction, the heart rate, synaptic transmission, the secretion of hormones, the initiation of muscle contraction, and numerous other physiological processes. Numerous toxic and therapeutic agents, including neurotoxins and anesthetic, antiepileptic, and antiarrhythmic drugs, exert their primary action on ionic channels. Although progress in biochemical characterization of a few ion channels has been made, the chemical composition of membrane structures controlling permeability remains unclear. My area of research seeks to reveal the molecular nature and organization of sodium and potassium channels through the application of specific chemical and pharmacological probes in voltage clamp experiments. Neurotoxins, anesthetic agents, and group-specific chemical reagents are used to modify channel function in specific ways. He sodium channel inactivation gating mechanism will be explored using amino group-specific chemical reagents, scorpion toxins, and channel blockers related to the action of local anesthetics. Potassium channel sites will be probed with specific chemical modifiers and with a scorpion toxin that binds tightly to the channel. The properties of potassium channels in nerve, muscle, and lymphocyte membranes will be compared, and factors that modulate the conductance and gating of potassium channels will be explored at whole cell and single channel levels. Surface charges will be probed using enzymes and peptide ionophores incorporated into the membrane to investigate the relationships among protein, lipid and carbohydrate constituents of the membrane. We will attempt to record from single ion channels in demylinated nerve fibers. The role of channel aggregation and distribution on functional channel properties will also be investigated. Through these studies, sites and receptors on ionic channels are mapped out, inferences can be made regarding the molecular nature of the normal channel gating process, useful ligands for chemical extraction and purification of ionic channels are characterized, and the molecular mechanisms of action for clinically important toxins and therapeutic agents are revealed.
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