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Vol. 57, Issue 2, 278-287, February 2000
-Adrenergic Receptor Signaling in
G
q-Mediated Cardiac Hypertrophy and Ventricular
Dysfunction
Departments of Medicine (G.W.D., G.W., S.B.L.) and Pharmacology
(G.W.D., N.M.T., A.Y., S.B.L.), University of Cincinnati College of
Medicine, Cincinnati, Ohio.
Targeted cardiac overexpression of the 
-subunit of the
heterotrimeric G protein Gq in transgenic mice evokes
hypertrophy and depressed stimulation of cardiac inotropy and
chronotropy by 
-adrenergic receptor (AR) agonists in vivo, which
is a hallmark of many forms of experimental and human heart failure.
The molecular basis of this AR dysfunction was explored in
transgenic mice overexpressing G
q ~5-fold over
background. Isoproterenol-stimulated adenylyl cyclase activities in
myocardial membranes were significantly depressed in Gq
mice compared with nontransgenic controls (19.7 ± 2.6 versus
43.7 ± 5.6 pmol/min/mg) without a decrease in AR expression
levels. Functional coupling of both AR subtypes was impaired.
Similarly, in whole-cell patch-clamp studies, AR stimulation of
L-type Ca2+ channel currents was depressed ~75% in the
Gq mice. Cardiac AR from these mice showed decreased
formation of the active high-affinity conformation
(RH = 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, AR kinase, protein
kinase C), only protein kinase C activity was elevated in
Gq 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 Gq mice. Pertussis
toxin treatment of isolated Gq myocytes resulted in an
improvement in AR, but not that of forskolin or NaF, stimulation of
adenylyl cyclase. Thus three distinct mechanisms contribute to impaired
AR 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
Gq signaling, the current work may be broadly applicable
to interfaces whereby modification of heart failure might be considered.
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