Catecholamine-Independent Heart Rate Increases Require Ca2+/Calmodulin-Dependent Protein Kinase II

Background—Catecholamines increase heart rate by augmenting the cAMP-responsive hyperpolarization-activated cyclic nucleotide-gated channel 4 pacemaker current (If) and by promoting inward Na+/Ca2+ exchanger current (INCX) by a “Ca2+ clock” mechanism in sinoatrial nodal cells (SANCs). The importance, identity, and function of signals that connect If and Ca2+ clock mechanisms are uncertain and controversial, but the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to β-adrenergic receptor (β-AR) stimulation. The aim of this study was to measure the contribution of the Ca2+ clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation. Methods and Results—We used the L-type Ca2+ channel agonist Bay K8644 (BayK) to activate the SANC Ca2+ clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from wild-type control mice. In contrast, SANCs and isolated hearts from mi...