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 language | English (US) |
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Pages (from-to) | 2458-2465 |
Number of pages | 8 |
Journal | Circulation |
Volume | 99 |
Issue number | 18 |
DOIs | |
State | Published - May 11 1999 |
Externally published | Yes |
Keywords
- Adrenergic
- Beta
- Contractility
- Phospholamban
- Receptors
- Relaxation
- Troponin I
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)