D2 dopamine receptors modulate Gα-subunit coupling of the CB1 cannabinoid receptor

CB1 cannabinoid (CB1) and D-2 dopamine (D-2) receptors are known to couple to the G protein Galpha(i/o). It has been reported that concurrent activation of D-2 receptors and CB1 receptors, in primary striatal neuronal culture, promotes functional CB1 receptor coupling to Galpha(s) resulting in elevations in intracellular cyclic AMP levels. We now report that in the absence of D-2 receptors, acute activation of CB1 receptors inhibits cyclic AMP accumulation, whereas the presence of D-2 receptors promotes CB1-stimulated cAMP accumulation, presumably through Galpha(s). This Galpha(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 CB1 receptor was sufficient to switch the coupling of the CB1 receptors from Galpha(i/o) to Galpha(s). Persistent activation of D-2 receptors resulted in heterologous sensitization of adenylate cyclase to subsequent stimulation by forskolin, whereas the persistent activation of CB1 receptors did not. Additional studies in human embryonic kidney cells cotransfected with D-2 and CB1 receptors revealed that persistent activation (18 h) of D-2 receptors induced a switch of CB1 receptor coupling from Galpha(s) to Galpha(i/o). This D-2 receptor-induced effect allowed for CB1 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 CB1 receptors.