Activation of type II adenylate cyclase by D-2 and D-4 but not D-3 dopamine receptors

The D-2-like dopamine receptors couple to a variety of signal transduction pathways, including inhibition of adenylate cyclase, mitogenesis, and activation of potassium channels. Although these effects are mediated via pertussis toxin-sensitive G proteins, G(i/o), it is likely that some of these effects are influenced by the release of G protein beta gamma subunits. Type II adenylate cyclase (ACII) is highly regulated by multiple biochemical stimuli, including protein kinase C, forskolin, G protein alpha subunits, and G protein beta gamma subunits. The ability of beta gamma subunits to activate this enzyme In the presence of activated alpha(s) has been particularly well characterized. Although stimulation by beta gamma subunits has been described as conditional on the presence of activated alpha(s), beta gamma subunits also potentiate ACII activity after activation of protein kinase C. We created stable cell lines expressing ACII and the D-2L receptor, the D-3 receptor, or the D-4.4 receptor. Activation of D-2L or D-4.4 receptors, but not D-3 receptors, potentiated beta-adrenergic receptor/G(s)-stimulated activity of ACII, as measured by the intracellular accumulation of cAMP. Similarly, stimulation of D-2L or D-4.4 receptors potentiated phorbol ester-stimulated ACII activity in the absence of activated alpha(s), whereas stimulation of D-3 receptors did not. The effect of D-2-like receptor stimulation was blocked by pretreatment with pertussis toxin and by inhibition of protein kinase C. We propose that activation of both D-2L and D-4.4 dopamine receptors potentiated phorbol-12-myristate-13-acetate-stimulated ACII activity through the release of beta gamma subunits from pertussis toxin-sensitive G proteins. In contrast, the lack of D-3 receptor-mediated effects suggests that stimulation of D-3 receptors does not result in an appreciable release of beta gamma subunits.