Localized cAMP-dependent signaling mediates β2-adrenergic modulation of cardiac excitation-contraction coupling

Ying Ying Zhou, Heping Cheng, Konstantin Y. Bogdanov, Charlene Hohl, Ruth Altschuld, Edward G. Lakatta, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

Recent studies have shown that β2-adrenergic receptor (β2-AR)- stimulated increases in the intracellular Ca2+ (Ca(i)) transient and contraction in cardiac myocytes are dissociated from the increase in adenosine 3',5'-cyclic monophosphate (cAMP) level and are not accompanied by an increase in phospholamban phosphorylation, an acceleration in relaxation, or a reduction in myofilament Ca2+ response. Thus we hypothesized that the β2-AR modulation of cardiac excitation-contraction (EC) coupling may be mediated by either a cAMP-independent mechanism or a compartmentalized cAMP pathway. To directly distinguish between these two possibilities, the responses of the L-type Ca2+ current (I(ca)), Ca(i) transient, and contraction to β2-AR as well as to β1-AR stimulation were examined in rat ventricular myocytes in the presence or absence of specific inhibitory cAMP analogs, Rp diastereomers of adenosine 3',5'-cyclic monophosphothioate (Rp- cAMPS) and 8-(4-chlorophenylthio)-cAMP (RpCPT-cAMPS). As expected, the positive inotropic effect induced by an adenylyl cyclase activator, forskolin (2 x 10-7 M), or a β1-AR agonist, norepinephrine (5 x 10-8 M) plus prazosin (10-6 M), was completely blocked by Rp-CPT-cAMPS. More importantly, the responses of I(ca), Ca(i) transient, and contraction to β2-AR stimulation by zinterol (10-5 M) or isoproterenol plus a selective β1-AR antagonist, CGP-20712A, were also entirely abolished by Rp-cAMPS (in the patch-pipette solution) or Rp-CPT-cAMPS (in the bath solution). In pertussis toxin-treated cells, although the response of cAMP was not altered, the β2-AR-stimulated increase in contraction amplitude was markedly enhanced and accompanied by a hastened relaxation, resulting in a tight association between cAMP and contraction. These results indicate that β2- AR modulation of cardiac excitation-contraction coupling requires cAMP. The dissociation of β2-AR-stimulated cAMP production and regulation of myofilament and sarcoplasmic reticulum functions is attributable to a functional compartmentation of the cAMP-dependent signaling due to an activation of β2-AR-coupled G(i) and/or G(o).

Original languageEnglish (US)
Pages (from-to)H1611-H1618
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume273
Issue number3 42-3
StatePublished - Oct 13 1997
Externally publishedYes

Keywords

  • Adenosine 3',5'-cyclic monophosphate compartmentation
  • Calcium current
  • Intracellular calcium
  • Pertussis toxin-sensitive G proteins
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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