D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture.
Dopamine (DA) regulation of intracellular cyclic AMP formation in purified, intact striatal neurons in primary culture was examined. DA (EC50, 3 microM) and vasoactive intestinal polypeptide (VIP; EC50, 10 nM) stimulated cyclic AMP formation by 2- and 5-fold, respectively. In the presence of 0.1 microM forskolin (which was virtually ineffective alone), neurohormone efficacy was augmented; potency was unaffected. In the presence of 0.1 microM SCH 23390, a selective D1 antagonist, the DA dose-response curve was shifted rightward in a competitive manner. At low concentrations (0.01-1.0 microM), however, DA inhibited basal cyclic AMP formation. The inhibitory effect, but not the shift of the dose-response curve, was blocked by 5 microM l-sulpiride, a selective D2 antagonist. At saturating concentrations of VIP (0.1-1.0 microM), no other neurohormone can further augment cyclic AMP formation. Under these conditions, increasing concentrations of DA resulted in a dose-dependent (IC50, 0.5 microM) inhibition of VIP-stimulated cyclic AMP synthesis. This effect was augmented in the presence of 0.1 microM SCH 23390 and blocked by 5 microM l-sulpiride. Sulpiride antagonism was stereospecific, with the l-isomer being 30-fold more potent than the d-isomer. The rank order of potency for a series of dopaminergic agonists and antagonists at the receptor mediating attenuation of cyclic AMP formation suggests that it is of the D2 type. Furthermore, both DA and Met-enkephalin inhibition of cyclic AMP formation is lost after exposure of striatal neurons to islet activator protein. These findings suggest that a D2 receptor mediates the inhibition of intracellular cyclic AMP formation by DA in striatal neurons in primary culture, and may do so by an interaction with the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.
Weiss
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S
Sebben
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Garcia-Sainz
J A
JA
Bockaert
J
J
D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis*; D004224:Diterpenes / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology* / Q000502:physiology; D018492:Dopamine Antagonists; D004622:Embryo, Mammalian; D007700:Kinetics; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000502:physiology*; D017448:Receptors, Dopamine D2; D012701:Serotonin / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D001427:Bacterial Toxins; D004224:Diterpenes; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D012701:Serotonin; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D004298:Dopamine