The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors

We tested the hypothesis that human CB1 cannabinoid receptors (hCB1) can se quester G(i)/(o)-proteins from a common pool and prevent other receptors fr om signaling. Human CB1 cannabinoid receptors were expressed in superior ce rvical ganglion (SCG) neurons by microinjection of hCB1 cDNA. Expression of hCB1 cannabinoid receptors abolished the Ca2+ current inhibition by endoge nous pertussis toxin-sensitive G(i)/(o) coupled receptors for norepinephrin e (NE) and somatostatin (SOM) but not by endogenous pertussis toxin-insensi tive G(s) coupled receptors for vasoactive intestinal polypeptide. Signalin g by NE was rescued by expression of G alpha(oB), G beta(1), and G gamma(3) . Expression of mGluR2 metabotropic glutamate receptors, another pertussis toxin-sensitive G-protein-coupled receptor, had no effect on the signaling by NE or SOM. Some hCB1 receptors were constitutively active because the ca nnabinoid receptor inverse agonist SR 141617A enhanced the Ca2+ current. So me hCB1 receptors also appear to be precoupled to G(i)/(o)-proteins because the cannabinoid agonist WIN 55,212-2 decreased the Ca2+ current at a time when no G-proteins were available to couple to alpha(2)-adrenergic and soma tostatin receptors. In SCG neurons microinjected with a lower concentration of hCB1 cDNA, the effect of SR 141716A was reduced, and the response to NE and SOM was partially restored. Subsequent to the application of SR 141716 A, the Ca2+ current inhibition by NE and SOM was abolished. These results s uggest that both the active and inactive states of the hCB1 receptor can se quester G(i)/(o)-proteins from a common pool. Cannabinoid receptors thus ha ve the potential to prevent other G(i)/(o)-coupled receptors from transduci ng their biological signals.