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 sequester G(i/o)-proteins from a common pool and prevent other receptors from signaling. Human CB1 cannabinoid receptors were expressed in superior cervical ganglion (SCG) neurons by microinjection of hCB1 cDNA. Expression of hCB1 cannabinoid receptors abolished the Ca(2+) current inhibition by endogenous pertussis toxin-sensitive G(i/o)-coupled receptors for norepinephrine (NE) and somatostatin (SOM) but not by endogenous pertussis toxin-insensitive G(s)-coupled receptors for vasoactive intestinal polypeptide. Signaling by NE was rescued by expression of Galpha(oB), Gbeta(1), and Ggamma(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 cannabinoid receptor inverse agonist SR 141617A enhanced the Ca(2+) current. Some hCB1 receptors also appear to be precoupled to G(i/o)-proteins because the cannabinoid agonist WIN 55,212-2 decreased the Ca(2+) current at a time when no G-proteins were available to couple to alpha(2)-adrenergic and somatostatin 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 141716A, the Ca(2+) current inhibition by NE and SOM was abolished. These results suggest that both the active and inactive states of the hCB1 receptor can sequester G(i/o)-proteins from a common pool. Cannabinoid receptors thus have the potential to prevent other G(i/o)-coupled receptors from transducing their biological signals.
Vásquez
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Department of Pharmacology, Medical College of Georgia, Augusta, Georgia 30912-2300, USA.
Lewis
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D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000502:physiology*; D002186:Cannabinoids / Q000494:pharmacology*; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D008845:Microinjections; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000502:physiology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D017481:Receptors, Somatostatin / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D048588:Benzoxazines; D002186:Cannabinoids; D018076:DNA, Complementary; D009025:Morpholines; D009281:Naphthalenes; D011941:Receptors, Adrenergic; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D018094:Receptors, Metabotropic Glutamate; D017481:Receptors, Somatostatin; D010566:Virulence Factors, Bordetella; C108822:metabotropic glutamate receptor 2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D009638:Norepinephrine