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beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart.
- Source :
-
Circulation [Circulation] 1999 May 11; Vol. 99 (18), pp. 2458-65. - Publication Year :
- 1999
-
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.<br />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.<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 99
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 10318670
- Full Text :
- https://doi.org/10.1161/01.cir.99.18.2458