Ca(2+)/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity and Sinoatrial Nodal Pacemaker Cell Energetics

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. AIMS: 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. METHODS AND 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 O(2) 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 O(2) 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.