Molecular Determinants for the Action of Psychostimulants

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DESCRIPTION (provided by applicant): The catecholamine dopamine (DA) plays a key role in the regulation of cognitive, emotional, and behavioral functions, and abnormalities in its regulation have been implicated in several psychiatric and neurological disorders. DA exerts it actions at D2-like and D1-like receptors, members of the G protein-coupled receptor (GPCR) family. DA reuptake by the DA transporter (DAT) is a principal mechanism for terminating dopaminergic transmission, and this protein is the primary molecular target of amphetamine, cocaine, and other psychostimulants. The Javitch laboratory studies structure-function relations and mechanisms of regulation of neurotransmitter transporters and related bacterial transporters, as well as mechanisms of dopamine receptor oligomerization and function. His long-term research goals are to: 1) Understand the structural bases of agonist and antagonist binding and specificity in G protein-coupled receptors, with a current focus on dopamine and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation. 3) Determine the structural bases of substrate translocation and inhibitor binding to the dopamine transporter. 4) Determine the mechanistic bases of amphetamine-induced dopamine efflux and the role of regulation of these processes in sensitization. The K Award enables the candidate to devote focused efforts to the exploration of new approaches, novel systems and various multidisciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. In collaboration with leading experts, individuals in the candidate's laboratory are now pursuing membrane protein crystallography and electron paramagnetic resonance & single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporter and are also pursuing work in knock-in mice and transgenic flies as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used to lay the groundwork to maintain the candidate's research at the leading edge of the field of molecular mechanisms of drug abuse and actions of antipsychotic drugs. The support of the K05 Award would play an essential role in the candidate's continued growth by giving him the flexibility to focus in part outside of the area of his current methodologies and to fuse his own professional growth with that of his research program and his trainees.