Abstract
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, Gi/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 αs has been particularly well characterized. Although stimulation by βγ subunits has been described as conditional on the presence of activated αs, βγ 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 β-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 αs, whereas stimulation of D3receptors 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 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.
Footnotes
- Received March 3, 1997.
- Accepted April 17, 1997.
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Send reprint requests to: Val J. Watts, Medical Research Service (151LL), VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97201. E-mail:wattsv{at}ohsu.edu
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This work was supported by the Johnson and Johnson Focused Giving Program, the Veterans Affairs Merit Review and Research Career Scientist Programs, a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression, and T32 DA07262.
- The American Society for Pharmacology and Experimental Therapeutics
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