Abstract
The cardiac muscarinic receptor (M2R) regulates heart rate, in part, by modulating the acetylcholine (ACh) activated K+ current IK,ACh through dissociation of G-proteins, that in turn activate KACh channels. Recently, M2Rs were noted to exhibit intrinsic voltage sensitivity, i.e. their affinity for ligands varies in a voltage dependent manner. The voltage sensitivity of M2R implies that the affinity for ACh (and thus the ACh effect) varies throughout the time course of a cardiac electrical cycle. The aim of this study was to investigate the contribution of M2R voltage sensitivity to the rate and shape of the human sinus node action potentials in physiological and pathophysiological conditions. We developed a Markovian model of the IK,ACh modulation by voltage and integrated it into a computational model of human sinus node. We performed simulations with the integrated model varying ACh concentration and voltage sensitivity. Low ACh exerted a larger effect on IK,ACh at hyperpolarized versus depolarized membrane voltages. This led to a slowing of the pacemaker rate due to an attenuated slope of phase 4 depolarization with only marginal effect on action potential duration and amplitude. We also simulated the theoretical effects of genetic variants that alter the voltage sensitivity of M2R. Modest negative shifts in voltage sensitivity, predicted to increase the affinity of the receptor for ACh, slowed the rate of phase 4 depolarization and slowed heart rate, while modest positive shifts increased heart rate. These simulations support our hypothesis that altered M2R voltage sensitivity contributes to disease and provide a novel mechanistic foundation to study clinical disorders such as atrial fibrillation and inappropriate sinus tachycardia.
Highlights
The cardiac muscarinic receptor (M2R) plays a crucial role in regulating heart rate variability and vulnerability to atrial arrhythmia by modulating the acetylcholine (ACh) activated K+ current IK,ACh
We recently proposed that relaxation gating represents a voltage dependent change in ACh affinity induced by voltage dependent conformational changes within M2R [5]
Based on the M2R voltage-dependent properties, we predict that subsaturating ACh concentrations exert a larger effect during diastolic membrane voltages, compared to the voltages during the cardiac action potentials (AP)
Summary
The cardiac muscarinic receptor (M2R) plays a crucial role in regulating heart rate variability and vulnerability to atrial arrhythmia by modulating the acetylcholine (ACh) activated K+ current IK,ACh. ACh activation of M2R triggers dissociation of the G beta-gamma subunits (Gβɣ) that in turn directly activate Kir 3.x subunits to conduct IK,ACh. Unexpectedly, M2Rs were discovered to possess an intrinsic ability to sense transmembrane voltage [2] and the affinity of the receptor for ligands was noted to vary in response to changes in membrane voltage [3]. The changes in affinity exert a downstream effect on the KACh channel such that the channel is more active (more current) at hyperpolarized potentials and less active (less current) at depolarized potentials. Relaxation gating refers to a time-dependent change in current magnitude following a depolarizing or hyperpolarizing voltage step [4] and has important consequences for shaping the cardiac action potentials (AP), especially in the sinus node. As a result of conformational changes in the M2R, the affinity for ACh varies throughout the cardiac electrical cycle such that low (subsaturating)
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