Effect of Dopamine on Activation of Rat Striatal Adenylate Cyclase by Free Mg2+ and Guanyl Nucleotides

John D. McSwigan, Susan E. Nicol, I. I. Gottesman, V. B. Tuason, William H. Frey

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18 Scopus citations

Abstract

Abstract: Stimulation of rat striatal adenylate cyclase by guanyl nucleotides was examined utilizing either MgATP or magnesium 5′‐adenylylimidodiphos‐phate (MgApp(NH) p) as substrate. GTP and 5′‐ guanylylimidodiphosphate (Gpp(NH) p) stimulate adenylate cyclase under conditions where the guanyl nucleotide is not degraded. The apparent stimulation of adenylate cyclase by GDP is due to an ATP‐dependent transphosphorylase present in the tissue which converts GDP to GTP. We conclude that GTP is the physiological guanyl nucleotide responsible for stimulation of striatal adenylate cyclase. Dopamine lowers the Ka for Gpp(NH) p stimulation twofold, from 2.4 μM to 1.2 μM and increases maximal velocity 60%. The kinetics of Gpp(NH) p stimulation indicate no homotropic interactions between Gpp(NH) p sites and are consistent with one nonessential Gpp(NH) p activator site per catalytic site. Double reciprocal plots of the activation by free Mg2+ were concave downward, indicating either two sets of sites with different affinities or negative cooperativity (Hill coefficient = 0.3, K0.5= 23 mM). The data conform well to a model for two sets of independent sites and dopamine lowers the Ka for free Mg2+ at the high‐affinity site threefold, from 0.21 mM to 0.07 mM. The antipsy‐chotic drug fluphenazine blocks this shift in Ka due to dopamine. Dopamine does not appreciably affect the affinity of adenylate cyclase for the substrate, MgApp(NH) p. Therefore, dopamine stimulates striatal adenylate cyclase by increasing the affinity for free Mg2+ and guanyl nucleotide and by increasing maximal velocity.

Original languageEnglish (US)
Pages (from-to)594-601
Number of pages8
JournalJournal of Neurochemistry
Volume34
Issue number3
DOIs
StatePublished - Mar 1980

Keywords

  • Adenylate cyclase
  • Dopamine
  • Fluphenazine
  • Guanyl nucleotides
  • Magnesium
  • Schizophrenia

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