Role of RGS7 in controlling behavioral responses to addictive drugs

描述（由申请人提供）：阿片类药物、可卡因和安非他明等药物通过激活纹状体中的多巴胺和阿片G蛋白偶联受体引起其大部分成瘾作用。通过这些受体的持续信号传导产生一系列分子适应，导致成瘾的发展。我们的长期目标是阐明调节纹状体G蛋白通路中信号传导的分子和细胞机制，这是理解导致物质依赖的事件和设计治疗纠正策略的必要前提。 在G蛋白信号传导途径中，表面受体在与神经递质结合后激活异源三聚体G蛋白，其进而调节许多形成细胞反应的分子的功能状态。越来越多的证据表明，G蛋白信号调节因子（Regulators of G protein Signaling，RGS）在调节G蛋白信号中起着重要作用。RGS蛋白限制G蛋白活性，从而控制神经递质信号传导的敏感性和程度。然而，我们对特定RGS蛋白在塑造G蛋白信号传导中所起作用的理解充其量是支离破碎的。 这个探索性建议的主要目的是探索一个研究不足的信号调节器，RGS7在控制成瘾药物的影响的潜在参与。我们的初步数据表明，RGS7在控制纹状体中的G蛋白信号传导中具有先前未预料到的作用。我们已经发现：（i）RGS7是一种有效的G蛋白抑制剂，作用于D2多巴胺和？阿片受体，（ii）它经历了由神经递质信号传导的变化引起的组成重排，和（iii）病毒介导的纹状体RGS7敲低增强了对可卡因的精神敏感性。我们假设RGS7与纹状体中的其他RGS蛋白和共同的结合伴侣共同作用，以控制对阿片类药物和可卡因的行为反应。拟议的研究将通过在纹状体回路中选择性破坏RGS7的小鼠模型并评估其药物诱导的行为来验证这一假设。预计了解RGS蛋白作用的机制，自然地抵消成瘾药物诱导的过度GPCR信号传导，将是开发旨在减少成瘾的有效疗法的核心。

DESCRIPTION (provided by applicant): Drugs such as opioids, cocaine and amphetamine elicit most of their addictive effects via activating dopamine and opioid G protein coupled receptors in the striatum. Persistent signaling through these receptors produce a range of molecular adaptations leading to the development of addiction. Our long term goal is to elucidate molecular and cellular mechanisms that regulate signaling in the striatal G protein pathways as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. In G protein signaling pathways, the surface receptors upon binding to the neurotransmitter activate heterotrimeric G proteins, which in turn regulate functional states of many molecules that shape cellular responses. Increasing evidence indicates that Regulators of G protein Signaling (RGS) proteins play essential roles in modulating G protein signaling. RGS proteins limit G protein activity and thereby control both sensitivity and extent of neurotransmitter signaling. However, our understanding of the role that specific RGS proteins play in shaping G protein signaling that contributes to addiction is fragmented at best. The main purpose of this exploratory proposal is to probe potential involvement of a poorly studied signaling regulator, RGS7 in controlling the effects of addictive drugs. Our preliminary data points to a previously unanticipated role of RGS7 in controlling G protein signaling in the striatum. We have found that: (i) RGS7 is a potent G protein inhibitor acting downstream from the D2 dopamine and ?-opioid receptors, (ii) it undergoes compositional rearrangement induced by changes in neurotransmitter signaling, and (iii) viral-mediated knockdown of RGS7 in the striatum enhances psychomotor sensitization to cocaine. We hypothesize that RGS7 acts in concert with other RGS proteins in the striatum and common binding partners to control behavioral response to opioids and cocaine. The proposed research will test this hypothesis by generating mouse models with selective disruption of RGS7 in striatal circuitry and evaluating their drug induced behavior. It is anticipated that understanding the mechanisms of RGS protein action that naturally counteract excessive GPCR signaling induced by addictive drugs, will be central for the development of effective therapies aimed at curtailing the addiction.