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

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Abstract
CB1 cannabinoid (CB1) and D2 dopamine (D2) receptors are known to couple to the G protein Gαi/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 Gαs 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 Gαs. This Gαs 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 Gαi/o to Gαs. 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 Gαs to Gαi/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.

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