Opioid Signaling and Regulators of G Protein Signaling

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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.