Ca2+-regulated-cAMP/PKA signaling in cardiac pacemaker cells links ATP supply to demand

Yael Yaniv, Magdalena Juhaszova, Alexey E. Lyashkov, Harold A. Spurgeon, Steven J. Sollott, Edward G. Lakatta

Research output: Contribution to journalArticle

Abstract

Rationale: In sinoatrial node cells (SANC), Ca2+ activates adenylate cyclase (AC) to generate a high basal level of cAMP-mediated/protein kinase A (PKA)-dependent phosphorylation of Ca2+ cycling proteins. These result in spontaneous sarcoplasmic-reticulum (SR) generated rhythmic Ca2+ oscillations during diastolic depolarization, that not only trigger the surface membrane to generate rhythmic action potentials (APs), but, in a feed-forward manner, also activate AC/PKA signaling. ATP is consumed to pump Ca2+ to the SR, to produce cAMP, to support contraction and to maintain cell ionic homeostasis. Objective: Since feedback mechanisms link ATP-demand to ATP production, we hypothesized that (1) both basal ATP supply and demand in SANC would be Ca2+-cAMP/PKA dependent; and (2) due to its feed-forward nature, a decrease in flux through the Ca2+-cAMP/PKA signaling axis will reduce the basal ATP production rate. Methods and results: O2 consumption in spontaneous beating SANC was comparable to ventricular myocytes (VM) stimulated at 3Hz. Graded reduction of basal Ca2+-cAMP/PKA signaling to reduce ATP demand in rabbit SANC produced graded ATP depletion (r2=0.96), and reduced O2 consumption and flavoprotein fluorescence. Neither inhibition of glycolysis, selectively blocking contraction nor specific inhibition of mitochondrial Ca2+ flux reduced the ATP level. Conclusions: Feed-forward basal Ca2+-cAMP/PKA signaling both consumes ATP to drive spontaneous APs in SANC and is tightly linked to mitochondrial ATP production. Interfering with Ca2+-cAMP/PKA signaling not only slows the firing rate and reduces ATP consumption, but also appears to reduce ATP production so that ATP levels fall. This distinctly differs from VM, which lack this feed-forward basal cAMP/PKA signaling, and in which ATP level remains constant when the demand changes.

Original languageEnglish (US)
Pages (from-to)740-748
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number5
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Keywords

  • Bioenergetics
  • Calcium-activated adenylyl cyclase
  • Constitutive basal PKA-dependent phosphorylation
  • Pacemaker automaticity
  • Respiration

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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