beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart.
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.


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.
D008841:Actin Cytoskeleton / Q000378:metabolism; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010764:Phosphorylase Kinase / Q000378:metabolism; D010762:Phosphorylase a / Q000378:metabolism; D010763:Phosphorylase b / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D012508:Sarcolemma / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides; D013873:Thionucleotides / Q000494:pharmacology; D019209:Troponin C / Q000378:metabolism; D000099211:Phospholamban