Function of cardiac M3 receptors.

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.