Abstract
The sinoatrial node is perhaps one of the most important tissues in the entire body: it is the natural pacemaker of the heart, making it responsible for initiating each-and-every normal heartbeat. As such, its activity is heavily controlled, allowing heart rate to rapidly adapt to changes in physiological demand. Control of sinoatrial node activity, however, is complex, occurring through the autonomic nervous system and various circulating and locally released factors. In this review we discuss the coupled-clock pacemaker system and how its manipulation by neurohumoral signaling alters heart rate, considering the multitude of canonical and non-canonical agents that are known to modulate sinoatrial node activity. For each, we discuss the principal receptors involved and known intracellular signaling and protein targets, highlighting gaps in our knowledge and understanding from experimental models and human studies that represent areas for future research.
Highlights
The heart’s natural pacemaker, the sinoatrial node (SAN), spontaneously initiates each heartbeat
Adenosine application activates an inwardly rectifying K+ current (IKAdo) that is mediated by the same G-protein signaling and coupled K+ channels as IKACh (Kir3.1/3.4) (Belardinelli et al, 1988). This has been demonstrated in the human isolated SAN where adenosine application decreases heart rate (HR) via A1 receptor (A1R)-induced G-protein regulated K+ (GIRK) channel activation, an effect that is abolished by GIRK channel blockade, implicating that the chronotropic response may be predominantly due to IKAdo rather than alternative intracellular pathways and targets (Li et al, 2017)
One could argue that the SAN is one of the most important tissues in the body, as it initiates each-and-every normal heartbeat
Summary
The heart’s natural pacemaker, the sinoatrial node (SAN), spontaneously initiates each heartbeat. Multiple M2R-mediated pathways have been shown in rabbit SAN cells to produce these effects over different time scales and with different ACh concentrations: activation of IKACh, inhibition of If, and inhibition of Ca2+-clock components (Accili et al, 1998).
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