PT  - JOURNAL ARTICLE
AU  - Clemente Vásquez
AU  - Deborah L. Lewis
TI  - The CB1 Cannabinoid Receptor Can Sequester G-Proteins, Making Them Unavailable to Couple to Other Receptors
AID  - 10.1523/JNEUROSCI.19-21-09271.1999
DP  - 1999 Nov 01
TA  - The Journal of Neuroscience
PG  - 9271--9280
VI  - 19
IP  - 21
4099  - http://www.jneurosci.org/content/19/21/9271.short
4100  - http://www.jneurosci.org/content/19/21/9271.full
SO  - J. Neurosci.1999 Nov 01; 19
AB  - We tested the hypothesis that human CB1 cannabinoid receptors (hCB1) can sequester Gi/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 Ca2+ current inhibition by endogenous pertussis toxin-sensitive Gi/o-coupled receptors for norepinephrine (NE) and somatostatin (SOM) but not by endogenous pertussis toxin-insensitive Gs-coupled receptors for vasoactive intestinal polypeptide. Signaling by NE was rescued by expression of GαoB, Gβ1, and Gγ3. 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 Ca2+current. Some hCB1 receptors also appear to be precoupled to Gi/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 α2-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 Ca2+ current inhibition by NE and SOM was abolished. These results suggest that both the active and inactive states of the hCB1 receptor can sequester Gi/o-proteins from a common pool. Cannabinoid receptors thus have the potential to prevent other Gi/o-coupled receptors from transducing their biological signals.