(Circulation. 1999;99:2458-2465.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
ß2-Adrenergic cAMP Signaling Is Uncoupled From Phosphorylation of Cytoplasmic Proteins in Canine Heart
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Md (M.K., Y.Y.Z., H.A.S., S.J.Z., E.G.L., R.P.X.), and Max Delbrück Center for Molecular Medicine, Cardiology, Berlin, Germany (S.B., P.K., E.G.K.).
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov
Background—Recent studies of ß-adrenergic receptor (ß-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to ß2-AR versus ß1-AR stimulation.
Methods and Results—The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to ß-AR subtype stimulation. In addition, many of these parameters and L-type Ca2+ current (ICa) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by ß1-AR stimulation could explain the resultant modulation of cardiac function, substantial ß2-AR–mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I, C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that ß2-AR–stimulated increases in both ICa and contraction were abolished by PKA inhibition. Thus, the ß2-AR–directed cAMP/PKA signaling modulates sarcolemmal L-type Ca2+ channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins.
Conclusions—These results indicate that the dissociation of ß2-AR signaling from cAMP regulatory systems is only apparent and that ß2-AR–stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.
Key Words: receptors, adrenergic, beta • contractility • relaxation • phospholamban • troponin I
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