title: Ca²+/calmodulin-dependent protein kinase II (CaMKII) activity and sinoatrial nodal pacemaker cell energetics.
abstract: : Ca(2+)-activated basal adenylate cyclase (AC) in rabbit sinoatrial node cells (SANC) guarantees, via basal cAMP/PKA-calmodulin/CaMKII-dependent protein phosphorylation, the occurrence of rhythmic, sarcoplasmic-reticulum generated, sub-membrane Ca(2+) releases that prompt rhythmic, spontaneous action potentials (APs). This high-throughput signaling consumes ATP.
  
  
  OBJECTIVE
  We have previously demonstrated that basal AC-cAMP/PKA signaling directly, and Ca(2+) indirectly, regulate mitochondrial ATP production. While, clearly, Ca(2+)-calmodulin-CaMKII activity regulates ATP consumption, whether it has a role in the control of ATP production is unknown.
  
  
  RESULTS
  We superfused single, isolated rabbit SANC at 37°C with physiological saline containing CaMKII inhibitors, (KN-93 or autocamtide-2 Related Inhibitory Peptide (AIP)), or a calmodulin inhibitor (W-7) and measured cytosolic Ca(2+), flavoprotein fluorescence and spontaneous AP firing rate. We measured cAMP, ATP and O2 consumption in cell suspensions. Graded reductions in basal CaMKII activity by KN-93 (0.5-3 µmol/L) or AIP (2-10 µmol/L) markedly slow the kinetics of intracellular Ca(2+) cycling, decrease the spontaneous AP firing rate, decrease cAMP, and reduce O2 consumption and flavoprotein fluorescence. In this context of graded reductions in ATP demand, however, ATP also becomes depleted, indicating reduced ATP production.
  
  
  CONCLUSIONS
  CaMKII signaling, a crucial element of normal automaticity in rabbit SANC, is also involved in SANC bioenergetics.
authors: Laboratory of Cardiovascular Science, Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors: Yael
authors: Y
authors: Yaniv
authors: Harold A
authors: HA
authors: Spurgeon
authors: Bruce D
authors: BD
authors: Ziman
authors: Edward G
authors: EG
authors: Lakatta
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D012849:Sinoatrial Node / Q000166:cytology* / Q000201:enzymology*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000255:Adenosine Triphosphate; D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000242:Cyclic AMP; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide