Brain Cannabinoid Receptor Signaling and Pharmacology

描述（由申请人提供）：脑CB 1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 CB 1大麻素受体的作用机制及其对 这些生理和病理生理功能是未知的。我们知道 CB 1大麻素受体抑制神经递质的释放， 神经元Ca ~（2+）和K ~+通道。我们的实验室发现CB 1大麻素受体 紧张性抑制神经元钙通道。我们有新的证据证明CB 1 受体不仅调节Ca 2+通道，而且还阻止其他G 蛋白偶联受体的信号传导。这种新型的抑制剂 cross-talk表明CB 1大麻素受体可以起主导作用， 受体阻止其他G蛋白偶联受体的信号。因此，在本发明中， 大麻素受体不仅可以影响神经元的活动， 具有紧张性活性或用激动剂刺激，但也可通过螯合G 蛋白质和阻止其他受体转导其生物学功能， 信号. G蛋白螯合的程度似乎与 CB 1受体密度。由于CB 1受体的密度高于任何 其他G蛋白偶联受体在大脑中的CB 1受体的能力， 阻止其他G蛋白偶联受体的信号传导可能是 在特定脑区的生理意义。我们的假设是 CB 1大麻素受体不仅调节特定的离子通道， 隔离G蛋白并阻止其他G蛋白偶联受体 信号尚不清楚G蛋白螯合是否与 CB 1大麻素受体的生理功能，以及G 蛋白质螯合是完全未知的。我们将决定 CB 1受体对G蛋白的螯合是生理相关的， CB 1受体隔离G蛋白的机制。 拟议的研究的具体目标将测试的假设， CB 1大麻素受体通过以下方式阻止其他受体的信号传导： 隔离G蛋白和CB 1的特定结构域 受体有助于紧张活性和CB 1大麻素的能力 受体来隔离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.