Functional M3 muscarinic acetylcholine receptors in mammalian hearts

In contrast to most peripheral tissues where multiple subtypes of muscarinic acetylcholine receptor (mAChR) coexist, with each of them playing its part in the orchestra of parasympathetic innervation, the myocardium has been traditionally considered to possess a single mAChR subtype. Although there is much evidence to support the notion that one receptor subtype (M2) orchestrates myocardial muscarinic transduction, there is emerging evidence that M1 and M3 receptors are also expressed and are of potential physiological, pathophysiological and pharmacological relevance. Clarifying this issue has a profound impact on our thinking about the cholinergic control of the heart function and disease and approaches to new drug development for the treatment of heart disease associated with parasympathetic dysfunction. This review article presents evidence for the presence of the M3 receptor subtype in the heart, and analyzes the controversial data from published pharmacological, functional and molecular studies. The potential roles of the M3 receptors, in parasympathetic control of heart function under normal physiological conditions and in heart failure, myocardial ischemia and arrhythmias, are discussed. On the basis of these considerations, we have made some proposals concerning the future of myocardial M3 receptor research.