Physiologic Analysis of Two GABAR Gamma2-Subunit Domains

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DESCRIPTION (provided by applicant): This proposal describes a 5-year-training program for the development of an academic career in neurology and epilepsy. The principal investigator has completed residency training in neurology at Washington University in St. Louis and will complete a clinical epilepsy fellowship at Washington University in June 2002. He will then expand upon his scientific skills as an Assistant Professor of Neurology in the Epilepsy Division at Vanderbilt University Medical School. This program will promote the command of electro physiology, as applied to epilepsy. Robert L. Macdonald, MD, PhD will mentor the principal investigator's scientific development. Dr. Macdonald is a recognized leader in the field of electro physiology. He is the Chair of Neurology and has trained numerous K08 recipients, post-doctoral fellows and graduate students. In addition, close interaction with faculty in the Department of Neuroscience will provide additional scientific and career advice. Research will focus on the physiology and pharmacology of the gamma amino butyric acid receptor type A (GABAAR), the main fast inhibitory ion channel in the central nervous system. The GABAAR is the target of several anti-epileptic drugs, is associated with point mutations in at least two forms of human familial epilepsy, and is hypothesized will have an altered modulation by zinc in temporal lobe epilepsy. The proposed experiments entail construction of mutant and chimeric GABAARs, expressing the recombinant receptors in cultured cells, and determining their physiological kinetic parameters by rapid-application of drugs to macropatches and by analysis of single channel currents. The Specific Aims include: 1) evaluating the physiology GABAAR containing the point mutations found in human epilepsy, 2) determining the effect of allosteric modulators on the same GABAAR mutants, 3) determining the binding domains of zinc, and 4) determining the effect of GABAAR modulators on zinc inhibition. The Neurology Department at Vanderbilt University provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the probability that the principal investigator will establish a scientific niche and embark upon a successful independent academic career.