Abstract

CB₁ cannabinoid (CB₁) and D₂ dopamine (D₂) receptors are known to couple to the G protein Gα_i/o. It has been reported that concurrent activation of D₂ receptors and CB₁ receptors, in primary striatal neuronal culture, promotes functional CB₁ receptor coupling to Gα_s resulting in elevations in intracellular cyclic AMP levels. We now report that in the absence of D₂ receptors, acute activation of CB₁ receptors inhibits cyclic AMP accumulation, whereas the presence of D₂ receptors promotes CB₁-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 D₂ receptor activation. Thus, coexpression of the D₂ receptor with the CB₁ receptor was sufficient to switch the coupling of the CB₁ receptors from Gα_i/o to Gα_s. Persistent activation of D₂ 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 D₂ and CB₁ receptors revealed that persistent activation (18 h) of D₂ receptors induced a switch of CB₁ receptor coupling from Gα_s to Gα_i/o. This D₂ receptor-induced effect allowed for CB₁ receptor-mediated inhibition of cyclic AMP accumulation. The present studies suggest D₂ receptors may have a significant modulatory role in determining the G protein coupling specificity of CB₁ receptors.