Function of cardiac M₃ receptors

Abstract

1. Since the initial identification of the M3 subtype of muscarinic acetylcholine receptors (M3-mAChR) in the heart, there have been increasing interest and advances in studies on the pathophysiological roles of M3-mAChR in the heart. Recent studies from several laboratories have provided compelling and solid evidence in support of the important roles of M3-mAChR in regulation and maintenance of cardiac function and in generation and progression of heart disease as well. 2. The functions of the cardiac M3-mAChR revealed thus far include (i) M3-mAChR regulation of heart rate and cardiac repolarization, (ii) modulation of inotropic effects, (iii) cytoprotection against ischaemic injuries of myocardium, (iv) regulation of cell-to-cell communication, and (v) participation in generation and maintenance of atrial fibrillation. 3. Signal transduction mechanisms underlying these pathophysiological functions have also been studied, which have allowed us to get insight into the following mechanistic aspects. (i) M3-mAChR activates a delayed rectifying K+ current I(KM3) to participate in cardiac repolarization, negative chronotropic actions, and anti-dysrhythmic (suppresses ischaemic dysrhythmias) as well as pro-dysrhythmic (facilitates atrial fibrillation) actions. (ii) M3-mAChR interacts with gap-junctional channel connexin 43 to maintain cell-cell communication and excitation propagation. (iii) M3-mAChR regulates intracellular phosphoinositide hydrolysis to improve cardiac contraction and haemodynamic function. (iv) M3-mAChR activate anti-apoptotic signalling molecules, enhances endogenous antioxidant capacity, and diminishes intracellular Ca2+ overload, all of which contribute to protecting the heart against ischaemic injuries. 4. This article provides an overview of the potential roles of the M3-mAChR in parasympathetic control of heart function under normal physiological conditions and in the setting of a variety of pathological processes including heart failure, myocardial ischaemia and dysrhythmias.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children

“…On the other hand, a physiological nighttime prolongation in QTc interval has been observed in healthy adults (35) and healthy children (36), a consequence of increased parasympathetic drive during this period. A direct parasympathetic-dependent modulation of ventricular repolarization has already been demonstrated both in vitro and in vivo (37,38). In the present study, although MQT was a function of NN in a circadian fashion, no significant nighttime MQTc lengthening was observed in any group, and no significant changes in night-to-day ΔMQTc were observed across immune status-classified groups.…”

A new potassium ion current induced by stimulation of M2-cholinoreceptors in fish atrial myocytes

“…These effects are particularly strong in pacemaker and atrial tissues. The M 2 muscarinic receptors prevail in the mammalian myocardium, although some M 3 receptors are also present and physiologically active (Pönicke et al, 2003;Wang et al, 2007). The even-numbered muscarinic receptors, including M 2 , are coupled to G i proteins and act via inhibition of adenylate cyclase and a subsequent decrease in cellular cAMP content (Dhein et al, 2001).…”

“…Effects of sympathetic activation are rapidly reversed by parasympathetic stimulation, despite the continued sympathetic tone via the 'accentuated antagonism' of the autonomic nerves (Levy, 1971). It is widely recognized that the main parasympathetic neurotransmitter, acetylcholine (ACh), induces negative chronotropic and inotropic effects mainly via the activation of the second subtype (M 2 ) of muscarinic cholinoreceptors, which prevails in the mammalian myocardium (Dhein et al, 2001), even though the involvement of M 3 cholinoreceptors in mediation of ACh effects has been recently confirmed (Abramochkin et al, 2012;Wang et al, 2007).…”

M3 Muscarinic Receptor Signaling Stabilizes a Novel Mutant Human Ether-a-Go-Go-Related Gene Channel Protein via Phosphorylation of Heat Shock Factor 1 in Transfected Cells

“…It also regulates cardiac AP repolarization and cell-to-cell communication. 22 Two subtypes of muscarinic receptors, M2-and M3-mAChR, have been reported to be expressed in HEK293 cells. 23 The M3-mAChR antagonist, 4-DAMP, but not the M2-mAChR antagonist, AF-DX116, abolished carbachol-induced maturation of the mutant hERG-FLAG, indicating the involvement of M3-mAChR.…”