Opioid Signaling and Regulators of G Protein Signaling

描述(由申请人提供)： 吗啡因其止痛作用而被广泛使用，尽管其复杂的药理作用存在许多临床问题。吗啡通过G蛋白偶联(GPCR)(阿片受体)的信号受细胞因素的调节，包括G蛋白信号(RGS)蛋白的调节。单个RGS蛋白能够通过GPCRs选择性地调节信号，但它们对(-阿片信号的特异性以及构成这种特异性的机制还没有很好的定义。我的假设是，RGS蛋白在阿片信号的负性调节中起重要作用，RGS蛋白的多样性对不同的G蛋白偶联受体具有特异性。这一假说将在HEK293细胞中进行检验，具体目的如下：1)鉴定在HEK293细胞中表达的RGS蛋白，2)研究单个RGS蛋白在调节(-阿片信号)中的作用，以及3)确定调节(-阿片信号)的RGS蛋白是固有的特异性还是能够通过其他Gi/o蛋白偶联受体调节信号。这项研究的结果将有助于理解RGS蛋白在调节多个具有重要生理意义的GPCR信号中所起的作用。这一知识将为未来RGS蛋白作用的靶向抑制剂或增强剂的开发提供基础。

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.