Trafficking in Human CB1 Cannabinoid Receptor Signaling

描述（由申请人提供）：大麻素激动剂，如δ 9-四氢大麻酚（δ 9-THC），大麻的主要精神活性成分，已被证明可缓解疼痛，并减少化疗引起的恶心和体重减轻。不幸的是，大麻素类药物也表现出令人不安的拟精神病副作用。我们的目标是开发大麻素药物，保留delta 9-THC的医学重要药理作用，但产生更少的副作用。在本提案中，我们计划利用一种新的，高灵敏度的实验方法，等离子体波导共振（PWR）光谱，以确定：a。结构上不同类别的大麻素激动剂是否稳定独特的大麻素受体构象;和，B.激动剂结合的CB 1大麻素受体构象是否表现出对G蛋白α-亚基的特异性;和/或，c. G蛋白β-γ亚基。我们已经证明，PWR技术是一个有价值的工具，以调查激动剂介导的结构变化G蛋白偶联受体，G蛋白类型的激动剂结合受体构象的亲和力，并评估激动剂结合GPCR激活个别G蛋白类型的能力。对单个G蛋白类型表现出选择性的大麻素药物的鉴定可以提供将大麻素的医学有用作用与其不良副作用分开的方法。

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.