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 pertussis toxin-sensitive G proteins, G(i/o), it is likely that some of these effects are influenced by the release of G protein betagamma 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 betagamma subunits. The ability of betagamma subunits to activate this enzyme in the presence of activated alpha(s) has been particularly well characterized. Although stimulation by betagamma subunits has been described as conditional on the presence of activated alpha(s), betagamma subunits also potentiate ACII activity after activation of protein kinase C. We created stable cell lines expressing ACII and the D2L receptor, the D3 receptor, or the D4.4 receptor. Activation of D2L or D4.4 receptors, but not D3 receptors, potentiated beta-adrenergic receptor/Gs-stimulated activity of ACII, as measured by the intracellular accumulation of cAMP. Similarly, stimulation of D2L or D4.4 receptors potentiated phorbol ester-stimulated ACII activity in the absence of activated alpha(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 D2L and D4.4 dopamine receptors potentiated phorbol-12-myristate-13-acetate-stimulated ACII activity through the release of betagamma 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 betagamma subunits.
Watts
V J
VJ
Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland 97201, USA. wattsv@ohsu.edu
Neve
K A
KA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
C493593:DRD3 protein, human; C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D019257:Quinpirole; D000242:Cyclic AMP; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D004298:Dopamine