Brain Cannabinoid Receptor Signaling and Pharmacology

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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.