Marijuana, the most commonly used illegal drug in the US, exerts its biological effects by activating endogenous cannabinoid receptors. The CB1 cannabinoid receptor is found in the central nervous system and is mediates marijuana's psychoactive properties. This project will elucidate the effects of Cannabinoid Receptor Interacting Protein 1A (CRIP1A) on cannabinoid receptor (CB1) signalling. The major goals of this study are to understand how CRIP1A modulates CB1 responses during acute and chronic agonist treatment. We will determine how CRIP1A affects G-protein activation, effector responses, receptor trafficking and receptor desensitization and downregulation. To understand how CRIP1A modulates receptor activation, human embryonic kidney cells heterologously transfected with the CB1 receptor, with or without CRIP1A co-transfection, will be utilized. CRIPIA's acute effects on high affinity agonist binding sites will be determined by competition of full and partial agonists for binding of the CB1 inverse agonist [3H]SR1. CRIPIA's effects on affects on CB1 mediated G protein activation will be examined using [35S]GTPgammaS binding assays, under conditions of both acute and chronic agonist stimulation. Immunoflorescent labeling will determine CRIPIA's effects on intracellular trafficking of CB1 receptors. The ability of CRIP1A to modulate effector activity in response to spontaneous CB1 activity will be examined in assays of cAMP formation and MAP kinase phosphorylation. Study of CB1 receptor regulation may be useful in the understanding and treatment of marijuana addiction, and in understanding the mechanisms of regulation of the endogenous cannabiniod system. In addition, therapeutic effects of cannabinoids in areas such as drug abuse, appetite, pain, spasticity, and cancer make them potential targets for drug development. A thorough understanding of the endocannabinoid system may allow the utilization of marijuana's therapeutic effects while decreasing the adverse psychoactive effects. In short, study of this system may open the door to new therapeutics for the treatment of drug addiction, obesity, pain and other neurological and psychiatric disorders. ? ? ?
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