TY - JOUR
T1 - Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells
AU - Vinogradova, Tatiana M.
AU - Brochet, Didier X.P.
AU - Sirenko, Syevda
AU - Li, Yue
AU - Spurgeon, Harold
AU - Lakatta, Edward G.
PY - 2010/9/17
Y1 - 2010/9/17
N2 - Rationale: Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na+-Ca2+ exchange current (INCX), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late diastolic depolarization INCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective: To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results: Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlated with the time to 90% decay of cytosolic Ca2+ transient (T-90C). Local SR Ca2+ depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca2+ refilling. Inhibition of SR Ca2+ 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-90C and proportionally shifted the LCR period and spontaneous cycle length (R2=0.98). Conclusions: The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca2+ replenishment, which is critically dependent on SR pumping rate, Ca2+ available for pumping, supplied by L-type Ca2+ channel, and ryanodine receptor Ca2+ release flux, each of which is modulated by cAMP-mediated protein kinase A-dependent phosphorylation.
AB - Rationale: Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na+-Ca2+ exchange current (INCX), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late diastolic depolarization INCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective: To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results: Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlated with the time to 90% decay of cytosolic Ca2+ transient (T-90C). Local SR Ca2+ depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca2+ refilling. Inhibition of SR Ca2+ 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-90C and proportionally shifted the LCR period and spontaneous cycle length (R2=0.98). Conclusions: The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca2+ replenishment, which is critically dependent on SR pumping rate, Ca2+ available for pumping, supplied by L-type Ca2+ channel, and ryanodine receptor Ca2+ release flux, each of which is modulated by cAMP-mediated protein kinase A-dependent phosphorylation.
KW - sarcoplasmic reticulum Ca pumping
KW - sinoatrial nodal pacemaker cells
KW - β-adrenergic receptor signaling
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U2 - 10.1161/CIRCRESAHA.110.220517
DO - 10.1161/CIRCRESAHA.110.220517
M3 - Article
C2 - 20651285
AN - SCOPUS:77957283607
VL - 107
SP - 767
EP - 775
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 6
ER -