Regulators of G-protein signaling (RGS) are GTPase accelerating proteins (GAP) that fine-tune the timing and intensity of G-protein coupled receptor (GPCR) signaling through negative regulation. RGS proteins play important pathophysiological roles in addiction, with three RGS proteins in particular highly expressed in the mesolimbic pathway (RGS2, RGS4, and RGS9-2). These subtypes have been shown to influence the signaling of key mu-opioid and dopamine receptors, and vary in expression levels in response to drugs of abuse such as morphine and cocaine. The study of individual subtypes in vivo can be difficult due to compensatory activity that gives rise to subtle phenotypes in knockout animals, as well as the highly conserved nature of their catalytic domains that makes it pharmacologically challenging to create selective small molecule ligands. We propose to create new optogenetic tools that will enable the bi-directional activation and inhibition of individual RGS subtypes in a spatio-temporally precise and cell-type specific manner. This type of dynamic RGS subtype-specific control in vivo will bring a major methodological advance toward our basic understanding of RGS roles in addiction and their validation as therapeutic targets and biomarkers, by powerfully bridging the molecular level intracellular signaling events and cell type-level neural circuit dynamics that together mechanistically underlie downstream addictive phenotypes.
Regulators of G-protein signaling (RGS) are GTPase accelerating proteins (GAP) that fine-tune the timing and intensity of G-protein coupled receptor (GPCR) signaling. They play important pathophysiological roles in addiction, with multiple subtypes that have been shown to influence the signaling of key mu-opioid and dopamine receptors, and vary in expression levels in response to drugs of abuse such as morphine and cocaine. However, methodological hurdles exist to establishing the brain region- and cell type-specific actions of individual RGS subtypes in vivo, thus presenting challenges in resolving their pathophysiological roles and evaluating them as therapeutic targets and biomarkers. Thus, to overcome these hurdles, we propose to create new optogenetic tools that will enable the bi-directional activation and inhibition of individual RGS subtypes in a spatio-temporally precise and cell-type specific manner. This type of dynamic RGS subtype- specific control in vivo will bring a major methodological advance by powerfully bridging the molecular level intracellular signaling events and cell type-level neural circuit dynamics that together mechanistically underlie downstream addictive phenotypes.
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