Fig. 5.
Schematic diagram illustrating the impact of LPS-induced sepsis on M2R-GIRK signaling in SAN tissue pacemaking and HRV. Upon M2R stimulation by a muscarinic agonist, CCh in SAN cells, the βγ subunit of the coupled G-protein directly activates outward K+ current (IKACh) via inwardly rectifying potassium (GIRK) channels, consisting of GIRK1 and GIRK4 heteromers, which results in K+ efflux and membrane hyperpolarization. Further downstream signaling leads to reduction in Ca2+ mobilization and contractility of SAN tissues and decrease in heart rate and increase in HRV. LPS-induced sepsis reduces expression of M2R, GIRK1, and GIRK4 channels, which diminishes the above-mentioned effects of CCh stimulation.