The main goal of this project is to use novel anesthetic and non- anesthetic compounds to determine which neurotransmitter receptors are candidates for site(s) of anesthetic action. To accomplish this, we will determine which receptors discriminate between these two classes of compounds. A second goal is to determine what properties are required for modulation of receptor function by correlating the physical properties (derived in part from computer modeling by Dr. Pohorille) of these compounds with their actions on neurotransmitter receptors. To allow comparison of different receptors in the same cell type, all receptors will be produced in Xenopus oocytes by expression of cDNAs, cRNAs, or mRNAs coding for specific receptor subtypes. Receptors to be studied are: GABA/A, glutamate (kainate and NMDA subtypes) and glycine. These receptors can be assembled from different subunits resulting in receptor subtypes with distinct drug sensitivities; we will determine which subunit combinations are anesthetic-sensitive or -resistant. In most cases, human receptors will be studied. Responses to neurotransmitter agonists will be determined electrophysiologically using a two-electrode voltage-clamp recording of membrane currents produced by receptor activation. We propose that these results will distinguish between three hypotheses: i. Action on only a single receptor consistently distinguishes anesthetics from non-anesthetics. ii. All anesthetics but no non-anesthetics affect several receptor system. iii. The effects of anesthetics and non-anesthetics (which can be divided into inactive and convulsant compounds) results from summation of action of excitatory and inhibitory systems.
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