%0 Journal Article %A Val J. Watts %A Ronald Taussig %A Rachael L. Neve %A Kim A. Neve %T Dopamine D2 Receptor-Induced Heterologous Sensitization of Adenylyl Cyclase Requires Gαs: Characterization of Gαs-Insensitive Mutants of Adenylyl Cyclase V %D 2001 %R 10.1124/mol.60.6.1168 %J Molecular Pharmacology %P 1168-1172 %V 60 %N 6 %X 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. %U https://molpharm.aspetjournals.org/content/molpharm/60/6/1168.full.pdf