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- W2914448404 abstract "Firing rate and rhythm of spontaneous action potentials (APs) in sinoatrial nodal cells (SANC) are controlled via the fidelity of clock coupling: rhythmic, spontaneous, local Ca2+ releases (LCRs) that emerges beneath the cell membrane (‘Ca2+ clock’) during diastole couples to sarcolemmal electrogenic mechanisms (‘membrane clock’). We hypothesized that dormant guinea pig SANC, i.e. cells that don’t fire spontaneous APs, represent an extreme form of clock uncoupling, and increased cAMP-mediated, PKA-dependent phosphorylation of the coupled-clock system proteins ignite rhythmic AP firing in dormant SANC. Membrane potential of dormant GP SANC averaged −38±1mV(n=46), ICaL, If, and IK current densities were comparable to those that fire spontaneous APs, and LCRs were small and random. Isoproterenol or CPT-cAMP led to de novo spontaneous AP generation in ∼50% of dormant SANC. The initial response involved increases in LCR size and rhythmicity and small amplitude, spontaneous APs and whole-cell Ca2+ transients. Average LCR size continued to increase, average LCR period shortened, partially synchronizing LCRs to late diastole, paralleled by MDP hyperpolarization to ∼-60 mV. AP cycle length shortened similar to LCR period. β-AR stimulation increased availability of ICaL and IK, and If. Inhibition of Ca2+ clock by CPA precluded the isoproterenol-induced AP generation in 91% of dormant SANC, but If block by ivabradine did not inhibit the activation. Ivabradine, however, prolonged the transition between dormant and steady firing state following the initiation of β-AR stimulation. When β-AR stimulation/CPT-cAMP was removed, all changes reversed in order and SANC again became dormant. At least in some SANC, dormancy represents membrane & Ca2+ clock uncoupling that is rescued via cAMP-mediated, PKA-induced increased function of both membrane and Ca2+ clock proteins." @default.
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- W2914448404 date "2019-02-01" @default.
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- W2914448404 title "Coupling of Calcium- and Membrane Clocks Ignites De Novo Spontaneous Action Potential in Dormant Guinea Pig Sinoatrial Nodal Cells via Camp-PKA Signaling" @default.
- W2914448404 doi "https://doi.org/10.1016/j.bpj.2018.11.1261" @default.
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