Activation of type II adenylate cyclase by D₂ and D₄ but not D₃ dopamine receptors

The D₂-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 pertussia toxin-sensitive G proteins, G(i/o) it is likely that some of these effects are influenced by the release of G protein βγ subunits. Type II adenylate cyclase (ACII) is highly regulated by multiple biochemical stimuli, including protein kinase C, forskolin, G protein α subunits, and G protein βγ subunits. The ability of βγ subunits to activate this enzyme in the presence of activated α(s) has been particularly well characterized. Although stimulation by βγ, subunits has been described as conditional on the presence of activated α(s) βγ subunits also potentiate ACII activity after activation of protein kinase C. We created stable cell lines expressing ACII and the D(2L) receptor, the D₃ receptor, or the D_4.4 receptor. Activation of D(2L) or D_4.4 receptors, but not D₃ receptors, potentiated β-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 α(s), whereas stimulation of D₃ receptors did not. The effect of D₂-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 βγ subunits from pertussis toxin-sensitive G proteins. In contrast, the lack of D₃ receptor-mediated effects suggests that stimulation of D₃ receptors does not result in an appreciable release of βγ subunits.