title: Ca2+-regulated-cAMP/PKA signaling in cardiac pacemaker cells links ATP supply to demand.
abstract: BACKGROUND
  In sinoatrial node cells (SANC), Ca(2+) activates adenylate cyclase (AC) to generate a high basal level of cAMP-mediated/protein kinase A (PKA)-dependent phosphorylation of Ca(2+) cycling proteins. These result in spontaneous sarcoplasmic-reticulum (SR) generated rhythmic Ca(2+) 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 Ca(2+) 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 Ca(2+)-cAMP/PKA dependent; and (2) due to its feed-forward nature, a decrease in flux through the Ca(2+)-cAMP/PKA signaling axis will reduce the basal ATP production rate.
  
  
  RESULTS
  O(2) consumption in spontaneous beating SANC was comparable to ventricular myocytes (VM) stimulated at 3 Hz. Graded reduction of basal Ca(2+)-cAMP/PKA signaling to reduce ATP demand in rabbit SANC produced graded ATP depletion (r(2)=0.96), and reduced O(2) consumption and flavoprotein fluorescence. Neither inhibition of glycolysis, selectively blocking contraction nor specific inhibition of mitochondrial Ca(2+) flux reduced the ATP level.
  
  
  CONCLUSIONS
  Feed-forward basal Ca(2+)-cAMP/PKA signaling both consumes ATP to drive spontaneous APs in SANC and is tightly linked to mitochondrial ATP production. Interfering with Ca(2+)-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.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland 21224-6825, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.forename: Magdalena
authors.initials: M
authors.lastname: Juhaszova
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Lyashkov
authors.forename: Harold A
authors.initials: HA
authors.lastname: Spurgeon
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sollott
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption; D010507:Periodicity; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D025261:Mitochondrial Proton-Translocating ATPases; D000262:Adenylyl Cyclases; D002118:Calcium