Brain Cannabinoid Receptor Signaling and Pharmacology

脑大麻素受体信号传导和药理学

• 批准号: 6628336
• 负责人: DEBORAH L LEWIS
• 金额: $ 31.98万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-10 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628336
• 关键词: Cannabis; G protein; beta adrenergic receptor; calcium channel; cannabinoid receptor; cannabinoids; endogenous opioid; enzyme activity; ganglions; gene targeting; genetically modified animals; hippocampus; immunocytochemistry; laboratory rat; neural inhibition; neuropharmacology; norepinephrine; potassium channel; protein kinase A; protein structure function; receptor coupling; somatostatin

DESCRIPTION (provided by applicant): Brain CB1 cannabinoid receptors are involved in pain perception, appetite stimulation, learning and memory, the tremor of multiple sclerosis and the rewarding effects of opiates. The basic mechanisms of action of the CB1 cannabinoid receptor and their contributions to these physiological and pathophysiological functions are unknown. We do know that CB1 cannabinoid receptors inhibit neurotransmitter release and modulate neuronal Ca2+ and K+ channels. Our lab found that CB1 cannabinoid receptors tonically inhibit neuronal Ca2+ channels. We have new evidence that CB1 receptors not only modulate Ca2+ channels but that they also prevent other G protein-coupled receptors from signaling. This novel type of inhibitory cross-talk demonstrates that CB1cannabinoid receptors can function as dominant receptors preventing other G protein-coupled receptors from signaling. Thus, the cannabinoid receptor can influence neuronal activity not only when it is tonically active or stimulated with an agonist but also by sequestering G proteins and preventing other receptors from transducing their biological signals. The degree of G protein sequestration appears to be related to the density of CB1 receptors. Since the density of CB1 receptors is higher than any other G protein-coupled receptor in the brain the ability of CB1 receptors to prevent signaling by other G protein-coupled receptors is likely to be of physiological significance in specific brain areas. Our overlying hypothesis is that CB1 cannabinoid receptors not only modulate specific ion channels but also sequester G proteins and prevent other G protein-coupled receptors from signaling. It is not known if G protein sequestration is relevant to the physiological functions of the CB1 cannabinoid receptor, and the mechanism of G protein sequestration is completely unknown. We will determine whether sequestration of G proteins by CB1 receptors is physiologically relevant and the mechanism by which CB1 receptors sequester G proteins. The specific aims of the proposed research will test the hypotheses that native CB1 cannabinoid receptors prevent other receptors from signaling by sequestering G proteins and that specific structural domains of the CB1 receptor contribute to tonic activity and the ability of CB1 cannabinoid receptor to sequester G proteins.

描述（由申请人提供）：大脑 CB1 大麻素受体是 参与疼痛感知、食欲刺激、学习和记忆 多发性硬化症的震颤和阿片类药物的奖励作用。基本的 CB1 大麻素受体的作用机制及其贡献 这些生理和病理生理功能尚不清楚。我们确实知道 CB1 大麻素受体抑制神经递质释放并调节 神经元 Ca2+ 和 K+ 通道。我们的实验室发现 CB1 大麻素受体 强效抑制神经元 Ca2+ 通道。我们有新的证据表明 CB1 受体不仅调节 Ca2+ 通道，而且还阻止其他 G 来自信号传导的蛋白质偶联受体。这种新型的抑制 串扰表明 CB1 大麻素受体可以发挥显性作用 受体阻止其他 G 蛋白偶联受体发出信号。因此， 大麻素受体不仅可以影响神经元活动 强直活性或用激动剂刺激，但也通过隔离 G 蛋白质并阻止其他受体转导其生物 信号。 G 蛋白隔离的程度似乎与 CB1受体的密度。由于 CB1 受体的密度高于任何受体 大脑中其他 G 蛋白偶联受体 CB1 受体的能力 阻止其他 G 蛋白偶联受体的信号传递可能是 特定大脑区域的生理意义。我们的首要假设是 CB1 大麻素受体不仅调节特定离子通道，而且 隔离 G 蛋白并防止其他 G 蛋白偶联受体 发信号。目前尚不清楚 G 蛋白隔离是否与 CB1大麻素受体的生理功能及G的作用机制 蛋白质隔离是完全未知的。我们将确定是否 CB1 受体对 G 蛋白的隔离具有生理相关性，并且 CB1 受体隔离 G 蛋白的机制。 拟议研究的具体目标将检验本地人的假设 CB1 大麻素受体通过以下方式阻止其他受体发出信号 隔离 G 蛋白和 CB1 的特定结构域 受体有助于补品活性和 CB1 大麻素的能力 隔离G蛋白的受体。