Dopamine D2 receptor-induced heterologous sensitization of adenylyl cyclase requires Gαs: Characterization of Gαs-insensitive mutants of adenylyl cyclase V

V. J. Watts, R. Taussig, R. L. Neve, K. A. Neve

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19 Scopus citations

Abstract

Whereas acute stimulation of Gαi/o-coupled receptors inhibits the activity of adenylyl cyclase, a delayed consequence of persistent activation of the receptors is heterologous sensitization, an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Gαs-coupled receptors. Gαs-insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Gαs-dependent activation of adenylyl cyclase. When adenylyl cyclase was stably expressed in human embryonic kidney (HEK) 293 cells with the D2L dopamine receptor, basal, forskolin-stimulated, and isoproterenol-stimulated cyclic AMP accumulation were all enhanced by 2-h pretreatment with the D2 receptor agonist quinpirole. Transient expression of wild-type adenylyl cyclase and three Gαs-insensitive mutants (F379L, R1021Q, and F1093S) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to β-adrenergic receptor-mediated activation of Gαs but that the mutants retained sensitivity to forskolin and to D2L receptor-mediated inhibition. Transiently expressed adenylyl cyclase V was robustly sensitized by 2-h pretreatment with quinpirole. In contrast, the Gαs-insensitive mutants displayed no sensitization of forskolin-stimulated cyclic AMP accumulation, indicating that responsiveness to Gαs is required for the expression of heterologous sensitization.

Original languageEnglish (US)
Pages (from-to)1168-1172
Number of pages5
JournalMolecular Pharmacology
Volume60
Issue number6
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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