Abstract
Spontaneous firing of sinoatrial (SA) node cells (SANCs) is regulated by cyclic adenosine monophosphate (cAMP)-mediated, protein kinase A (PKA)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from ryanodine receptors (RyR). The LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates the DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation, and suppresses normal spontaneous firing of SANCs. The cAMP-degrading PDE1, PDE3, and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by 3-isobutyl-1-methylxanthine (IBMX) increases spontaneous firing of SANC by ∼50%. Though inhibition of single PDE1–PDE4 only moderately increases spontaneous SANC firing, dual PDE3 + PDE4 inhibition produces a synergistic effect hastening the spontaneous SANC beating rate by ∼50%. Here, we describe the expression and distribution of different PDE subtypes within rabbit SANCs, several specific targets (L-type Ca2+ channels and phospholamban) regulated by basal concurrent PDE3 + PDE4 activation, and critical importance of RyR Ca2+ releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in striated patterns inside SANCs strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.
Highlights
The sinoatrial (SA) node, the primary physiological pacemaker of the heart, drives more than 3 billion heartbeats during a human life span
The local Ca2+ releases (LCRs) activate an inward INCX, which exponentially accelerates the rate of diastolic depolarization (DD), prompting the “Membrane clock” to generate the action potential (AP) (Bogdanov et al, 2001; Sanders et al, 2006; Lakatta et al, 2010)
The sarcoplasmic reticulum (SR)-generated LCRs can occur independent of concurrent changes in the membrane potential; they persist during the voltage clamp of the cell membrane or in permeabilized SA node pacemaker cells (SANCs) (Vinogradova et al, 2004; Lakatta et al, 2010), manifesting the intracellular SR Ca2+ cycling “Ca2+ clock” in the absence of the “Membrane clock.”
Summary
The sinoatrial (SA) node, the primary physiological pacemaker of the heart, drives more than 3 billion heartbeats during a human life span. The dynamic interaction of the “Ca2+ clock” and “Membrane clock” permits a high level of mutual entrainment between two individual clocks on a beat-to-beat basis (Figures 1A,B) This clock entrainment provides an additional degree of flexibility and robustness to the generation of spontaneous APs by the cardiac pacemaker cells (Lakatta et al, 2010; Yaniv et al, 2015). This basal AC activity is independent of constitutive β-adrenergic receptor (β-AR) activation, since neither the β1-AR antagonist, CGP-20712A, nor the β2-AR inverse agonist, ICI 118,551 affect the spontaneous SANCs beating rate (Vinogradova et al, 2006; Lakatta et al, 2010) Both the “Membrane clock” and “Ca2+ clock” are regulated by cAMP and cAMP-mediated PKAdependent phosphorylation. Evidence for compartmentalization of cAMP signaling in cardiac pacemaker cells under basal conditions is discussed
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