Regulation of Striatal GPCR Signaling

G蛋白偶联受体（GPCR）信号转导通路在纹状体，一个主要的奖励- 大脑中的处理核，在药物成瘾的发展中起着关键作用。许多滥用药物 包括阿片类药物和精神兴奋剂通过激活纹状体表达的GPCR产生作用， 神经元我们的长期目标是阐明调节细胞信号传导的分子和细胞机制， 纹状体GPCR是理解导致物质依赖的事件的必要先决条件， 设计治疗矫正的策略。 越来越多的证据表明，G蛋白信号转导调节因子（RGS）蛋白质在免疫调节中起着至关重要的作用。 控制与成瘾有关的GPCR途径。RGS蛋白用于抑制G蛋白信号传导，因此 被最佳地定位以自然地抵消由滥用药物引起的GPCR的过度激活。小 靶向RGS蛋白的分子治疗剂正成为有前景的治疗策略。但 RGS在调节纹状体G蛋白途径中的作用机制知之甚少。这项建议 重点是描绘关键纹状体RGS的分子，细胞和行为机制， 蛋白质：R7-RGS复合物调节纹状体神经元中的信号传导。在过去的一段时间里， 在理解R7-RGS方面取得了实质性进展，包括解决其高分辨率结构，定义其G 蛋白质的选择性和识别cAMP是参与其作用的关键第二信使系统。 这些观察依赖于我们开发的用于研究纹状体GPCR的许多创新工具和方法 以高精度发送信号。 基于积累的数据，我们假设通过G 蛋白质Gao通过变构调节的多环腺苷酸环化酶与下游cAMP产生效应物腺苷酸环化酶结合， 亚基R7-RGS复合物对成瘾药物的行为作用具有重要影响。这一假设将是 通过追求三个互补的特定目标进行测试，这些目标旨在（1）描述RGS - Gao的功能作用 轴在控制cAMP动力学，（2）确定结构/功能机制的RGS复杂的组织 （3）探讨RGS-Gao在控制阿片类药物反应中的行为和回路相关性， 精神兴奋剂为实现这些目标而提出的战略需要将遗传、 生物化学和生理学方法，利用存在的一系列强大的试剂，动物， 模型和创新的检测方法，可以检查体内信号的变化。

G protein Coupled Receptor (GPCR) signal transduction pathways in the striatum, a major reward- processing nucleus in the brain, play a pivotal role in the development of drug addiction. Many drugs of abuse including opioids and psychostimulants produce their effects by activating GPCRs expressed by striatal neurons. Our long-term goal is to elucidate molecular and cellular mechanisms that regulate signaling of the striatal GPCRs as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. Increasing evidence suggests that Regulators of G Protein Signaling (RGS) proteins play a crucial role in controlling GPCR pathways implicated in addiction. RGS proteins serve to curb G protein signaling and thus are optimally positioned to naturally counteract excessive activation of GPCRs by drugs of abuse. Small molecule therapeutics targeting RGS proteins are emerging as promising therapeutic strategies. However, the mechanisms of RGS action in regulation of striatal G protein pathways are poorly understood. This proposal is focused on delineating the molecular, cellular and behavioral mechanisms by which key striatal RGS protein: the R7-RGS complex regulates signaling in striatal neurons. During the previous period, we made substantial progress in understanding R7-RGS including solving its high-resolution structure, defining its G protein selectivity and identification of cAMP to be critical second messenger system involved in its effects. These observations relied on a host of innovative tools and approaches we developed to study striatal GPCR signaling with high degree of precision. Based on accumulated data we hypothesize that control of opioid and dopamine receptor signaling via G Protein Gao to the downstream cAMP producing effector, adenylate cyclase by allosterically regulated multi- subunit R7-RGS complexes critically shapes behavioral actions of addictive drugs. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) delineate functional role of RGS - Gao axis in controlling cAMP dynamics, (2) determine structure/functional mechanics of RGS complex organization and (3) probe behavioral and circuit relevance of RGS-Gao in controlling responses to opioids and psychostimulants. The strategy proposed to address these Aims will entail a synergistic combination of genetic, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents, animal models, and innovative assays that allow examining signaling changes in vivo.