Abstract
The sinoatrial (SA) node is the physiological pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and cardiac myocardium, degrading cAMP and, consequently, regulating basal cardiac pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock pacemaker system modulated by dual PDE3 + PDE4 activation and provide evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the basal cardiac pacemaker function and provides control over normal spontaneous beating of SANCs through (PDE3 + PDE4)-dependent modulation of local subsarcolemmal Ca2+ releases (LCRs).
Highlights
The sinoatrial (SA) node, the primary physiological pacemaker of the heart, is responsible for generation of every normal heartbeat, and during a human lifespan, the SA node creates more than 2.8 billion heartbeats
We first provide a brief overview of the “coupled-clock” pacemaker system that drive SA node automaticity, to introduce the primary targets for modulation of the SA node beating rate by basal PDE activation. This is followed by description of high basal level of cAMP in cardiac pacemaker cells created by constitutive adenylyl cyclase (AC) activation and consequent augmentation of phosphorylation by protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) of proteins involved in the generation of SA node automaticity
The resting rate of the human heart is generated by the SA node, i.e., automaticity of human sinoatrial nodal cells (SANC), which is driven by the coupled-clock pacemaker system regulated by Ca2+-cAMP-PKA signaling [137]
Summary
The sinoatrial (SA) node, the primary physiological pacemaker of the heart, is responsible for generation of every normal heartbeat, and during a human lifespan, the SA node creates more than 2.8 billion heartbeats. We first provide a brief overview of the “coupled-clock” pacemaker system that drive SA node automaticity, to introduce the primary targets for modulation of the SA node beating rate by basal PDE activation. This is followed by description of high basal level of cAMP in cardiac pacemaker cells created by constitutive adenylyl cyclase (AC) activation and consequent augmentation of phosphorylation by protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) of proteins involved in the generation of SA node automaticity. It should be mentioned that there are important differences between cell types in various regions of the heart (e.g., SANC vs. atrial or ventricular myocytes) based on their diverse cardiac function, which can lead to variations in the PDE-dependent modulation of ion channels and SR Ca2+ cycling
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