Molecular determinants for the action of psychostimulants

描述（申请人提供）：儿茶酚胺多巴胺（DA）在认知、情绪和行为功能的调节中起关键作用。其调节异常与药物滥用以及一些精神和神经疾病有关。DA作用于G蛋白偶联受体（GPCR）家族的d2样受体和d1样受体。DA转运体（DAT）的DA再摄取是终止多巴胺能传递的主要机制，该蛋白是安非他明、可卡因和其他精神兴奋剂的主要分子靶点。Javitch实验室主要研究神经递质转运体及相关细菌转运体的结构-功能关系和调控机制，以及多巴胺受体寡聚和功能的机制。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，目前主要研究DA和阿片受体。2)确定激动剂结合如何被转导成g蛋白激活和阻滞蛋白募集和信号传导。3)利用生物物理和结构方法与计算分析并行，确定底物转运和抑制剂与神经递质转运结合的结构基础，以及与转运相关的动力学。4)确定amph诱导的DA外排的机制基础以及这些过程在致敏和药物滥用中的调节作用。K奖使候选人能够专注于探索新方法，新系统和各种多学科方法，并致力于实验室研究计划的中心目标之一-药物滥用机制。该候选人的实验室正在研究膜蛋白晶体学、电子顺磁共振和细菌神经递质转运同源物的单分子荧光光谱。这项工作现在正在扩展到活细胞中受体的单分子成像。该实验室还在进行转基因果蝇和小鼠的研究，作为在生理背景下探索分子和机制的模型系统。这些新方法正在开发和使用，以保持候选人的研究在药物滥用和抗精神病药物作用的分子机制领域的领先地位。K05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扩展他的研究方法，将自己的专业成长与他的研究计划融合在一起，并为他的学员和初级教师提供广泛的指导。

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.