In:
Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 3 ( 2011-06), p. 379-387
Abstract:
Catecholamines increase heart rate by augmenting the cAMP-responsive hyperpolarization-activated cyclic nucleotide-gated channel 4 pacemaker current ( I f ) and by promoting inward Na + /Ca 2+ exchanger current ( I NCX ) by a “Ca 2+ clock” mechanism in sinoatrial nodal cells (SANCs). The importance, identity, and function of signals that connect I f and Ca 2+ clock mechanisms are uncertain and controversial, but the multifunctional Ca 2+ /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 Ca 2+ clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation. Methods and Results— We used the L-type Ca 2+ channel agonist Bay K8644 (BayK) to activate the SANC Ca 2+ 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 mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs but increased L-type Ca 2+ current ( I Ca ) equally in all SANCs, indicating that increasing I Ca was insufficient and suggesting that CaMKII activation was required for heart rate increases by BayK. BayK did not increase I f or protein kinase A-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca 2+ by BayK did not augment cAMP/protein kinase A signaling at these targets. Late-diastolic intracellular Ca 2+ release and I NCX were significantly reduced in AC3-I SANCs, and the response to BayK was eliminated by ryanodine in all groups. Conclusions— The Ca 2+ clock is capable of supporting physiological fight-or-flight responses, independent of β-AR stimulation or I f increases. Complete Ca 2+ clock and β-AR stimulation responses require CaMKII.
Type of Medium:
Online Resource
ISSN:
1941-3149
,
1941-3084
DOI:
10.1161/CIRCEP.110.961771
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2011
detail.hit.zdb_id:
2425487-3
