Brain Cannabinoid Receptor Signaling and Pharmacology

描述(申请人提供)：脑CB1类大麻素受体 参与痛觉、食欲刺激、学习和记忆， 多发性硬化症的震颤和鸦片类药物的奖励作用。最基本的 CB1大麻素受体的作用机制及其在脑损伤中的作用 这些生理和病理生理功能是未知的。我们知道 CB1大麻素受体抑制神经递质的释放和调节 神经细胞的钙、钾通道。我们的实验室发现CB1大麻素受体 紧张性抑制神经细胞钙通道。我们有新的证据表明CB1 受体不仅调节钙离子通道，而且还阻止其他G 来自信号的蛋白质偶联受体。这种新型的抑制性物质 串扰显示CB1类大麻素受体可以起主导作用 阻止其他G蛋白偶联受体发出信号的受体。因此， 大麻素受体不仅可以影响神经元的活动，还可以影响神经元的活动 紧张活跃的或用激动剂刺激的，但也通过隔离G 蛋白质和防止其他受体转导其生物 信号。G蛋白的隔离程度似乎与 CB1受体密度。由于CB1受体的密度比任何 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可能是 在特定的大脑区域具有生理意义。我们最重要的假设是 CB1大麻素受体不仅调节特定的离子通道，而且还 隔离G蛋白并阻止其他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 蛋白质的隔离是完全未知的。我们将确定是否 CB1受体对G蛋白的隔离在生理上是相关的 CB1受体隔离G蛋白的机制。 拟议研究的具体目标将检验本土化的假设 CB1大麻素受体通过以下途径阻止其他受体发出信号 隔离G蛋白和CB1特定结构域 受体参与紧张性活动和CB1类大麻素的能力 受体，以隔离G蛋白。

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.