Opioid Signaling and Regulators of G Protein Signaling

描述（由申请人提供）： 吗啡因其止痛特性而被广泛使用，尽管其复杂的药理学存在许多临床问题。吗啡通过G蛋白偶联（GPCR）α-阿片受体的信号传导受包括G蛋白信号传导（RGS）蛋白的调节剂在内的细胞因子调节。单个RGS蛋白能够通过GPCR选择性地调节信号传导，但它们对α-阿片样物质信号传导的特异性和构成这种特异性的机制还没有很好地确定。这是我的假设，RGS蛋白是重要的阿片信号的负调控和RGS蛋白的多样性赋予不同的G蛋白偶联受体的特异性。该假设将在HEK 293细胞中进行测试，如以下具体目的所述：1）鉴定HEK 293细胞中表达的RGS蛋白，2）研究单个RGS蛋白在调节β-阿片样物质信号传导中的作用，和3）确定调节β-阿片样物质信号传导的RGS蛋白是否具有固有特异性或能够通过其他Gi/o蛋白偶联受体调节信号传导。这项研究的结果将有助于了解RGS蛋白在调节多种生理重要GPCR信号传导中的作用。这些知识将为将来开发RGS蛋白作用的靶向抑制剂或增强剂提供基础。

DESCRIPTION (provided by applicant): Morphine is widely utilized due to its pain relieving properties, though its complex pharmacology presents many clinical problems. Morphine signaling through G-protein coupled (GPCR) (-opioid receptors is modulated by cellular factors including regulators of G-protein signaling (RGS) proteins. Individual RGS proteins are capable of regulating signaling selectively through GPCRs but their specificity for ((-opioid signaling and mechanisms constituting this specificity are not well defined. It is my hypothesis that RGS proteins are important for the negative regulation of opioid signaling and the diversity of RGS proteins confers specificity for different G-protein coupled receptors. This hypothesis will be tested in HEK293 cells as outlined in these specific aims: 1) to identify the RGS proteins expressed in HEK293 cells, 2) to investigate the role of individual RGS proteins in modulating (-opioid signaling, and 3) to determine if the RGS proteins that regulate (-opioid signaling are inherently specific or are capable of regulating signaling through other Gi/o protein coupled receptors. The results of this research will contribute to the understanding of the role RGS proteins play in modulating the signaling of multiple physiologically important GPCRs. This knowledge will provide a basis for future development of targeted inhibitors or enhancers of RGS protein action.