Emerging Regulatory Mechanisms in Sinoatrial Node Automaticity

Figures

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  FIGURE 1. The morphological and action potential characteristics of mouse SAN pacemaker cells (SAN PCs) and working cardiomyocytes. (A) SAN PCs are distinguished morphologically from working cardiomyocytes. These specialised cells are long, thin cells with few striations. (B) The APs of PCs are markedly different from those of the working cardiomyocytes (ACMs and VCMs), characterised by diastolic phase 4 depolarisation, also known as the “pacemaker potential”. The scale bar = 10 μm. The cell isolation and APs recording of SAN PCs, ACMs, and VCMs were performed as our previously described [21, 32]. ACM, atrial cardiomyocyte; VCM, ventricular cardiomyocyte.

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  FIGURE 2. Regulatory network governing SAN automaticity. This schematic depicts the coupled‐clock system underlying sinoatrial node (SAN) pacemaking. The synergistic coupling between the membrane voltage clock (M clock) and the calcium clock (Ca2+ clock) generates spontaneous depolarisations, which are modulated by pacemaker cell‐microenvironment crosstalk, glutamatergic signalling, and molecular regulators. SAN pacemaker cells‐fibroblast crosstalk promotes aerobic glycolysis via aldolase C (Aldoc), while glutamatergic signalling enhances local calcium releases (LCRs) through mitochondrial reactive oxygen species (ROS)‐Ca2+ coupling, leading to the activation of oxidised Ca2+/calmodulin‐dependent protein kinase II (Ox‐CaMKII). Several key molecular regulators include cold‐inducible RNA‐binding protein (CIRP), which under stress prevents pathological cAMP accumulation; Shugoshin‐1 (SGO1), stabilising HCN4 channels to augment the hyperpolarisation‐activated current (I f) current; and glucagon‐like peptide‐1 receptor (GLP‐1R) signalling, which potentiates I f via cAMP/PKA‐dependent HCN4 phosphorylation. ANS, autonomic nervous system; EAAT1, excitatory amino acid transporter 1; Glu, glutamate;…