Trafficking in Human CB1 Cannabinoid Receptor Signaling

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DESCRIPTION (provided by applicant): Cannabinoid agonists, such as delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive component of marijuana, have been demonstrated to relieve pain, and to reduce chemotherapy-induced nausea and weight loss. Unfortunately, cannabinoid drugs also exhibit disturbing psychotomimetic side effects. Our goal is to develop cannabinoid Pharmaceuticals that retain the medically important pharmacological effects of delta9-THC, but produce fewer side effects. In the present proposal we plan to utilize a novel, highly sensitive experimental method, plasmon-waveguide resonance (PWR) spectroscopy to determine: a. whether structurally different classes of cannabinoid agonists stabilize unique cannabinoid receptor conformations; and, b. whether agonist-bound CB1 cannabinoid receptor conformations exhibit specificity for G protein alpha-subunits; and/or, c. G protein beta-gamma-subunits. We have already demonstrated that the PWR technique is a valuable tool to investigate agonist-mediated structural changes in G protein-coupled receptors, to measure the affinity of G protein types to the agonist-bound receptor conformations and to assess the ability of agonist-bound GPCRs to activate individual G protein types. Identification of cannabinoid drugs that exhibit selectivity for individual G protein types may provide the means to separate the medically useful effects of cannabinoids from their undesirable side effects.