Molecular Determinants for the Action of Psychostimulants

描述（由申请人提供）：儿茶酚胺多巴胺（DA）在认知、情感和行为功能的调节中起关键作用，其调节异常与几种精神和神经疾病有关。DA作用于D2样和D1样受体，即G蛋白偶联受体（GPCR）家族成员。DA转运蛋白（DAT）的DA重摄取是终止多巴胺能传递的主要机制，该蛋白是苯丙胺、可卡因和其他精神兴奋剂的主要分子靶点。Javitch实验室研究神经递质转运蛋白和相关细菌转运蛋白的结构-功能关系和调节机制，以及多巴胺受体寡聚化和功能的机制。他的长期研究目标是：1）了解G蛋白偶联受体中激动剂和拮抗剂结合和特异性的结构基础，目前重点是多巴胺和阿片受体。2)确定激动剂结合如何被转换成G蛋白激活。3)确定底物转运和抑制剂与多巴胺转运蛋白结合的结构基础。4)确定安非他明诱导多巴胺外排的机制基础和这些过程在致敏中的调节作用。K奖使候选人能够集中精力探索新方法，新系统和各种多学科方法以及旨在实验室研究计划的中心目标之一的合作-滥用药物的机制。与领先的专家合作，候选人实验室的个人现在正在追求神经递质转运蛋白的细菌同系物的膜蛋白晶体学和电子顺磁共振和单分子荧光光谱学，并且还在敲入小鼠和转基因苍蝇中进行工作，作为模型系统来探测生理背景中的分子和机制见解。这些新的方法正在开发和使用奠定基础，以保持候选人的研究在药物滥用和抗精神病药物的作用的分子机制领域的前沿。K 05奖的支持将在候选人的持续成长中发挥重要作用，使他能够灵活地专注于他目前方法领域之外的部分领域，并将他自己的专业成长与他的研究计划和他的学员融合在一起。

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.