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Vol. 60, Issue 6, 1168-1172, December 2001

ACCELERATED COMMUNICATION
Dopamine D2 Receptor-Induced Heterologous Sensitization of Adenylyl Cyclase Requires Galpha s: Characterization of Galpha s-Insensitive Mutants of Adenylyl Cyclase V

Val J. Watts, Ronald Taussig, Rachael L. Neve, and Kim A. Neve

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan (R.T.); Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts (R.L.N.); Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon (K.A.N); and Medical Research Service, Veterans Affairs Medical Center, Portland, Oregon (K.A.N.)

Whereas acute stimulation of Galpha i/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 Galpha s-coupled receptors. Galpha s-insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galpha s-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 Galpha s-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 beta -adrenergic receptor-mediated activation of Galpha s 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 Galpha s-insensitive mutants displayed no sensitization of forskolin-stimulated cyclic AMP accumulation, indicating that responsiveness to Galpha s is required for the expression of heterologous sensitization.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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