Model schematic for ANS, CRBT and LCR in mouse SANC.

Abstract

During each heartbeat, SANC FR is determined by coupled interactions between the MO linked to sarcolemmal ionic currents, and the CO associated with SR Ca2+ release (JRel) and uptake (Jup). Over the course of a day and night cycle, the properties of MO and CO in SANC are tightly regulated by the ANS, CRBT, and LCR to generate circadian variations in FR. The ANS is regulated by the master circadian clock—SCN. Simultaneous SNA (orange dots) and PNA (blue dots) co-modulate a diverse range of subcellular targets in SANC and exhibit non-additive effects via cAMP-PKA dependent or independent pathways [6]. CRBT regulates the autonomic balance between SNA and PNA, influencing the kinetics and/or conductance of ion channels, exchangers, and pumps. LCR (green dots) within the SANC nucleus leads to circadian variations in the expression levels of ion channels, e.g., IHCN. In aged mice, SANC pacemaking function is disrupted by aging-dependent ion channel remodeling, intracellular Ca2+ cycling alternation, PNA impairment, and CRBT disruption (red dots) [25,26,39–41]. INa1.1, Na+ channel isoform Nav1.1 current; INa1.5, Na+ channel isoform Nav1.5 current; Ist, sustained inward Na+ current; INab, background Na+ current; Ito, transient component of 4-Aminopyridine-sensitive current; Isus, sustained component of 4- Aminopyridine-sensitive current; IKr, rapid delayed rectifying K+ current; IKs, slow delayed rectifying K+ current; IK1, inward rectifier K+ current; IKb, background K+ current; IKACh, muscarinic K+ current; ICaL, L-type Ca2+ channel current; ICaT, T-type Ca2+ channel current; INCX, Na+/Ca2+ exchanger current; ICab, background Ca2+ current; INaK, Na+/K+ pump current; IHCN, hyperpolarization-activated cyclic nucleotide–gated channel current; JSR, junctional sarcoplasmic reticulum; NSR, network sarcoplasmic reticulum; Jdiff, Ca2+ diffusion flux from subspace to cytoplasm compartment; JRel, Ca2+ release from JSR to subspace compartment; Jtr, Ca2+ transfer flux from NSR to JSR; Jup, SERCA Ca2+ pump flux. The CRBT icon is derived from https://openclipart.org/detail/231080/thermometer, while the circadian clock icon is modified based on https://openclipart.org/detail/198766/mono-tool-timer.</p