RT Journal Article SR Electronic T1 Mechanisms of Impaired β-Adrenergic Receptor Signaling in Gαq-Mediated Cardiac Hypertrophy and Ventricular Dysfunction JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 278 OP 287 VO 57 IS 2 A1 Gerald W. Dorn II A1 Nicole M. Tepe A1 Guangyu Wu A1 Atsuko Yatani A1 Stephen B. Liggett YR 2000 UL http://molpharm.aspetjournals.org/content/57/2/278.abstract AB Targeted cardiac overexpression of the α-subunit of the heterotrimeric G protein Gq in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by β-adrenergic receptor (βAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this βAR dysfunction was explored in transgenic mice overexpressing Gαq ∼5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in Gαqmice compared with nontransgenic controls (19.7 ± 2.6 versus 43.7 ± 5.6 pmol/min/mg) without a decrease in βAR expression levels. Functional coupling of both βAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, βAR stimulation of L-type Ca2+ channel currents was depressed ∼75% in the Gαq mice. Cardiac βAR from these mice showed decreased formation of the active high-affinity conformation (R H = 29% versus 62% for nontransgenic littermates), confirming a receptor-Gs-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, βAR kinase, protein kinase C), only protein kinase C activity was elevated in Gαq mouse hearts. Type V adenylyl cyclase was decreased ∼45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular Gs levels were unaltered, Gi2 and Gi3 were increased in Gαq mice. Pertussis toxin treatment of isolated Gαq myocytes resulted in an improvement in βAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired βAR function by in vivo Gq signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased Gαq signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered. The American Society for Pharmacology and Experimental Therapeutics