β2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart

Meike Kuschel, Ying Ying Zhou, Harold A. Spurgeon, Sabine Bartel, Peter Karczewski, Sheng Jun Zhang, Ernst Georg Krause, Edward G. Lakatta, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Recent studies of β-adrenergic receptor (β-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 β2-AR versus β1-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 β-AR subtype stimulation. In addition, many of these parameters and L-type Ca2+ current (I(ca)) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA- dependent phosphorylation cascade activated by β1-AR stimulation could explain the resultant modulation of cardiac function, substantial β2-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 β2-AR-stimulated increases in both I(Ca) and contraction were abolished by PKA inhibition. Thus, the β2-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 β2-AR signaling from cAMP regulatory systems is only apparent and that β2-AR-stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation- contraction coupling.

Original languageEnglish (US)
Pages (from-to)2458-2465
Number of pages8
JournalCirculation
Volume99
Issue number18
DOIs
StatePublished - May 11 1999
Externally publishedYes

Keywords

  • Adrenergic
  • Beta
  • Contractility
  • Phospholamban
  • Receptors
  • Relaxation
  • Troponin I

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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