Regulation of Striatal Signaling by RGS Proteins

描述(申请人提供)：纹状体中的G蛋白信号转导通路在药物成瘾的发展中起着关键作用。包括阿片类药物和精神刺激剂在内的许多滥用药物都是通过激活纹状体中的G蛋白来产生效果的，纹状体是大脑中主要的奖赏处理核。我们的长期目标是阐明调节纹状体G蛋白通路信号的分子和细胞机制，作为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。越来越多的证据表明，G蛋白信号转导调节蛋白(RGS)在控制与成瘾有关的G蛋白信号转导通路中起着至关重要的作用。RGS蛋白用于抑制G蛋白信号，因此处于最佳位置，自然地抵消滥用药物对G蛋白偶联受体的过度激活。以RGS蛋白为靶点的小分子疗法正在成为一种有前途的治疗策略。然而，RGS在调节纹状体G蛋白通路中的作用机制尚不清楚。这项建议的重点是描绘关键的纹状体RGS蛋白：RGS9-2和RGS7调节细胞信号的机制。我们最近的发现表明，这两个RGS蛋白的功能紧密交织在一起。它们以大分子复合体的形式存在，与几个结合伙伴结合，并在药物暴露时发生显着的重塑，以及神经元兴奋性的变化，表明RGS系统的可塑性有助于导致成瘾的分子适应。根据积累的初步数据，我们假设纹状体RGS9-2和RGS7与其结合伙伴合作，差异地调节从阿片受体和多巴胺受体到中心下游效应器腺酰环化酶的G蛋白信号，该系统的可塑性是成瘾药物作用的关键决定因素。这一假说将通过追求三个互补的特定目标来检验，这三个目标寻求(1)确定纹状体RGS复合体调节cAMP的机制，(2)了解其作用的受体和G蛋白的选择性，以及(3)测试CaMKII？调节纹状体RGS复合体的可塑性。为解决这些目标而提出的战略将需要遗传、行为、生化和生理方法的协同组合，利用一系列强大的试剂和动物模型的存在。

DESCRIPTION (provided by applicant): G protein signal transduction pathways in the striatum play a pivotal role in the development of drug addiction. Many drugs of abuse including opioids and psychostimulants produce their effects by activating G proteins in the striatum, a major reward-processing nucleus in the brain. 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. Increasing evidence suggests that Regulators of G protein Signaling (RGS) proteins play a crucial role in controlling G protein signaling pathways implicated in addiction. RGS proteins serve to curb G protein signaling and thus are optimally positioned to naturally counteract excessive activation of the G protein coupled receptors 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 mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Based on accumulated preliminary data we hypothesize that striatal RGS9-2 and RGS7 in cooperation with their binding partners differentially regulate G protein signaling from opioid and dopamine receptors to the central downstream effector adenylyl cyclase and that the plasticity in this system is a critical determinant of the addictive drug actions. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) to determine mechanisms of cAMP regulation by striatal RGS complexes, (2) understand receptor and G protein selectivity of their action and (3) test the role CaMKII? in regulating plasticity of striatal RGS complexes. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models.