1. beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart.
- Author
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Kuschel M, Zhou YY, Spurgeon HA, Bartel S, Karczewski P, Zhang SJ, Krause EG, Lakatta EG, and Xiao RP
- Subjects
- Actin Cytoskeleton metabolism, Adrenergic Agents pharmacology, Animals, Calcium-Binding Proteins metabolism, Cardiotonic Agents pharmacology, Cyclic AMP analogs & derivatives, Cyclic AMP pharmacology, Cyclic AMP-Dependent Protein Kinases physiology, Dogs, Imidazoles pharmacology, Isoquinolines pharmacology, Muscle Relaxation drug effects, Norepinephrine pharmacology, Phosphorylase Kinase metabolism, Phosphorylase a metabolism, Phosphorylase b metabolism, Phosphorylation drug effects, Receptors, Adrenergic, beta-1 drug effects, Receptors, Adrenergic, beta-1 physiology, Receptors, Adrenergic, beta-2 drug effects, Reserpine pharmacology, Sarcolemma metabolism, Second Messenger Systems drug effects, Thionucleotides pharmacology, Troponin C metabolism, Cyclic AMP physiology, Heart drug effects, Myocardial Contraction drug effects, Myocardium metabolism, Protein Processing, Post-Translational drug effects, Receptors, Adrenergic, beta-2 physiology, Second Messenger Systems physiology, Sulfonamides
- Abstract
Background: Recent studies of beta-adrenergic receptor (beta-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 beta2-AR versus beta1-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 beta-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 beta1-AR stimulation could explain the resultant modulation of cardiac function, substantial beta2-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 beta2-AR-stimulated increases in both ICa and contraction were abolished by PKA inhibition. Thus, the beta2-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 beta2-AR signaling from cAMP regulatory systems is only apparent and that beta2-AR-stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.
- Published
- 1999
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