In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 6 ( 2010-09-17), p. 767-775
Abstract:
Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca 2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na + -Ca 2+ exchange current ( I NCX ), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca 2+ transient and LCR appearance, defines the time of late diastolic depolarization I NCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective: To determine dependence of the LCR period on SR Ca 2+ refilling kinetics and establish links between regulation of SR Ca 2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results: Spontaneous APs and SR luminal or cytosolic Ca 2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca 2+ following AP-induced Ca 2+ transient was highly correlated with the time to 90% decay of cytosolic Ca 2+ transient (T-90 C ). Local SR Ca 2+ depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca 2+ refilling. Inhibition of SR Ca 2+ pump by cyclopiazonic acid dose-dependently suppressed spontaneous SANCs firing up to ≈50%. Cyclopiazonic acid and graded changes in phospholamban phosphorylation produced by β-adrenergic receptor stimulation, phosphodiesterase or protein kinase A inhibition shifted T-90 C and proportionally shifted the LCR period and spontaneous cycle length ( R 2 =0.98). Conclusions: The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca 2+ replenishment, which is critically dependent on SR pumping rate, Ca 2+ available for pumping, supplied by L-type Ca 2+ channel, and ryanodine receptor Ca 2+ release flux, each of which is modulated by cAMP-mediated protein kinase A–dependent phosphorylation.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.110.220517
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2010
detail.hit.zdb_id:
1467838-X
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