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. Abnormalities in its regulation have been implicated in drug abuse as well as 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 relationships 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 DA and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation and arrestin recruitment and signaling. 3) Determine the structural bases of substrate translocation and inhibitor binding to neurotransmitter transporters and the dynamics associated with transport using biophysical and structural approaches in parallel with computational analysis. 4) Determine the mechanistic bases of AMPH-induced DA efflux and the role of regulation of these processes in sensitization and substance abuse. The K Award enables the candidate to devote focused effort to the exploration of new approaches, novel systems and various multi-disciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. The candidate's laboratory is pursuing membrane protein crystallography and electron paramagnetic resonance & single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporters. This work is now being extended to single molecule imaging of receptors in living cells. The lab is also pursuing work in genetically modified flies and mice as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used 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 on expanding his research methodologies and to fuse his own professional growth with that of his research program as well as extensive mentorship of his trainees and junior faculty.