NEUROCHEMICAL ACTIONS OF PSYCHOTROPIC DRUGS

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DESCRIPTION(Adapted from applicant's abstract): The long term goal of this application over the past 30 years has been to elueidate molecular signaling systems in the brain whieh may be relevant to aetions of psyehotropic drugs. We propose continuing a characterization of multiple systems but with a special foeus on three: D-serine, neuronal nitric oxide synthase (nNOS) associated proteins, and higher inositol polyphosphates. (1) D-serine: We will extend our evidence for D-serine as a neuromodulator serving as the endogenous ligand for NMDA-glutamate receptors. We will eharaeterize serine racemase, the enzyme we have recently purified and cloned, which converts L- to D-serine. We will develop knockouts and transgenics for serine racemase and d-amino aeid oxidase, the enzyme which appears to physiologically degrade D-serine. (2) nNOS Associated Proteins-Focus on CAPON: CAPON is a nNOS associated protein we discovered, which may serve as a scaffold linking nNOS to other proteins. We recently discovered interactions of CAPON with synapsin, a synaptie vesicle protein, and Dexrasl, a new member of the Ras family. We will continue our studies implicating CAPON as a bridge delivering NO formed by nNOS to synapsin to affect synaptic vesiele funetion, and to Dexrasl to influenee its downstream signaling to alter nuelear funetion. (3) Higher Inositol Polyphosphates: Higher inositol polyphosphates are pyrophosphates with e about :-rgetic phosphate groups that we think may mediate phosphate transfer to proteins, perhaps assoeiated with synaptic vesicle turnover. We will extend our studies in which we purified and cloned IP 6 kinase, which forms the pyrophosphate PP-IPs (IP7 ). We will characterize functions of this enzyme and a related protein, PiUS that also possesses IP6 kinase activity. We will characterize putative protein phosphorylation by PP-IP 5. We will also complete purif aboutcation and cloning of PP-IPs kinase which forms bis PP-IP4, which contains two pyrophosphate groups