The orchestrated activity of voltage-gated ion channels enables cells in the nervous system,and throughout biology, to generate and propagate electrical signals. A primary focus of the laboratory is to investigate the structure of voltage-gated potassium channels and to understand how structural rearrangements in the voltage-sensing domains open and close the ion conduction pore. We have been using large-scale scanning mutagenesis to explore the secondary and tertiary structure of elements within the voltage-sensing domains. Using the structure of the KcsA potassium channel as a guide, we have begun to map the protein-protein interface between voltage-sensing and pore domains. Another approach exploits protein toxins that modify voltage-dependent gating to probe the structure and mechanics of regions involved in gating. Up to this point our work on the toxins has involved studying the mechanism by which these toxins modify gating, solving the three-dimensional structure of the toxins (through collaboration), and mapping their receptors. We are now beginning to use these gating modifier toxins to address fundamental questions about the structures involved in gating and on the type of conformational rearrangements that occur with changes in membrane voltage. In addition, the laboratory is also interested in understanding how the molecular design of voltage-gated ion channels allows them to fulfill specific physiological roles. We have been developing new pharmacological probes against specific types of voltage-gated ion channels so that their functional contribution to complex electrical phenomena can be better examined.
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