Ca2+/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.