D2 Dopamine Receptors Modulate Gα-Subunit Coupling of the CB1 Cannabinoid Receptor

CB 1 cannabinoid (CB 1 ) and D 2 dopamine (D 2 ) receptors are known to couple to the G protein Gα i/o . It has been reported that concurrent activation of D 2 receptors and CB 1 receptors, in primary striatal neuronal culture, promotes functional CB 1 receptor coupling to Gα s resulting in elevations in intracellular cyclic AMP levels. We now report that in the absence of D 2 receptors, acute activation of CB 1 receptors inhibits cyclic AMP accumulation, whereas the presence of D 2 receptors promotes CB 1 -stimulated cAMP accumulation, presumably through Gα s . This Gα s subunit switching was not prevented by pertussis toxin treatment and occurred in the presence and absence of D 2 receptor activation. Thus, coexpression of the D 2 receptor with the CB 1 receptor was sufficient to switch the coupling of the CB 1 receptors from Gα i/o to Gα s . Persistent activation of D 2 receptors resulted in heterologous sensitization of adenylate cyclase to subsequent stimulation by forskolin, whereas the persistent activation of CB 1 receptors did not. Additional studies in human embryonic kidney cells cotransfected with D 2 and CB 1 receptors revealed that persistent activation (18 h) of D 2 receptors induced a switch of CB 1 receptor coupling from Gα s to Gα i/o . This D 2 receptor-induced effect allowed for CB 1 receptor-mediated inhibition of cyclic AMP accumulation. The present studies suggest D 2 receptors may have a significant modulatory role in determining the G protein coupling specificity of CB 1 receptors.