CLONING AND CHARACTERIZATION OF CANNABINOID RECEPTORS

大麻是目前滥用最广泛的非法药物。然而，它的功能意义 健康和疾病中的大麻素受体系统包括使用大麻素作为镇痛剂， 癌症患者的止吐药物、抗癫痫和抗青光眼药物以及 免疫调节剂。到目前为止，已鉴定出两种大麻素受体亚型cbt和cb2。 通过cdna克隆，还发现了阿南达胺以及外源性的复杂药理性质。 这两个亚类并不能完全定义大麻素。阿南达胺能产生全系列的行为 对CBI受体基因敲除小鼠的影响(抗伤害性、嗜睡症和运动能力受损)。在……里面 此外，在这些小鼠的脑膜中可以诱导出由ANANDAME刺激的GTPyS活性。 最后，放射性配基结合研究表明，在脑和脊髓中存在额外的结合位点。 这个项目的目标是识别和表征大麻素受体的其他亚型。 以阐明它们在体内的作用。第一个具体目标是描述候选孤立GPCR的特征 大麻素受体活性。GPR55最近被确定为候选的大麻素受体，并且 我们有证据表明GPR35具有大麻素受体活性。GPR18是纳豆酰甘氨酸的受体， 一种内源性大麻。GPR119是油酰乙醇胺的受体， 棕榈酰乙醇胺。我们建议通过表达这些候选大麻素受体来表征这些受体 异源细胞系，允许详细描述配体的选择性和信号转导。第二 特定目标将识别具有大麻素受体活性的其他孤儿GPCRs 克隆战略。在特定的目标3中，我们将研究新型大麻素受体的功能作用。 这个目标中的实验旨在利用我们与其他Center Grant研究人员在 为了了解候选大麻素受体的功能作用。这些研究将有助于 涉及大麻素系统的新治疗策略的设计。此外，对 大麻素受体激活的分子机制可能有助于更好地理解 大麻在人类中的滥用。

Marijuana is currently the most widely abused illegal drug. However, the functional significance of the cannabinoid receptor system in health and disease includes the use of cannabinoids as analgesics, antiemetics in cancer patients, anticonvulsants for epilepsy and as antiglaucoma agents as well as immunomodulatory agents. To date, two cannabinoid receptor subtypes, CBt and CB2, have been identified by cDNA cloning, yet the complex pharmacological properties of anandamide as well as exogenous cannabinoids are not fully defined by these two subtypes. Anandamide produces the full range of behavioral effects (antinociception, catalepsy and impaired locomotor activity) in CBi receptor knockout mice. In addition, anandamide-stimulated GTPyS activity can be elicited in brain membranes from these mice. Finally, radioligand binding studies indicate the existence of additional binding sites in brain and spinal cord. The goal of this project is to identify and characterize additional subtypes of the cannabinoid receptors in order to elucidate their role in vivo. The first specific aim is to characterize candidate orphan GPCRs for cannabinoid receptor activity. GPR55 has recently been identified as a candidate cannabinoid receptor, and we have evidence that GPR35 has cannabinoid receptor activity. GPR18 is a receptor for Narachinoylglycine, an endocannabinoid. GPR119 is a receptor for oleoylethanolamide and palmitoylethanolamide. We propose to characterize these candidate cannabinoid receptors by expression in heterologous cell lines, allowing the detailed characterization of ligand selectivity and signaling. The second specific aim will identify additional orphan GPCRs with cannabinoid receptor activity using an expression cloning strategy. In specific aim 3, we will investigate the functional role of novel cannabinoid receptors. The experiments in this aim are designed to utilize our collaborations with other Center Grant Investigators in order to understand the functional roles of the candidate cannabinoid receptors. These studies will facilitate the design of new therapeutic strategies involving the cannabinoid system. Furthermore, insight into the molecular mechanisms of activation of cannabinoid receptors may lead to a better understanding of marijuana abuse in humans.