The fundamental goal of the proposed research is to elucidate mechanisms of receptor modulation, focussing primarily on the GABA/A receptor of the vertebrate central nervous system. The proposed study has two major parts. First, we propose to extend our preliminary observations that indicate that Ca2+ ions play a fundamental role in modulating the function of the GABA receptor, with the aim of determining the mechanism whereby Ca2+ influences GABA receptor function. In particular, we will confirm or reject a model in which calcium plays a role as an obligatory cofactor in the process of GABA stimulated C1- transport. Secondly, we will carry out electrophysiological and radioligand binding studies to test a theoretical model relating electrophysiological and biochemical parameters of modulator action. In particular, we will determine whether it is possible to predict efficacy of modulators of the GABA response on the basis of binding kinetics. Our long-term goals are to construct molecular models of the interaction of neuromodulators with the GABA/A receptor and to gain an understanding of the molecular underpinnings of GABA/A receptor function. These studies are expected to provide the basis for modeling of the relationship between the GABA receptor and its various modulatory sites, and may yield novel insights into the molecular mechanisms underlying the function of ligand-gated anion channels.
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