The Role of Muscarinic Acetylcholine Receptor M3 in Cardiovascular Diseases

Abstract

The muscarinic acetylcholine receptor M₃ (M₃-mAChR) is involved in various physiological and pathological processes. Owing to specific cardioprotective effects, M₃-mAChR is an ideal diagnostic and therapeutic biomarker for cardiovascular diseases (CVDs). Growing evidence has linked M₃-mAChR to the development of multiple CVDs, in which it plays a role in cardiac protection such as anti-arrhythmia, anti-hypertrophy, and anti-fibrosis. This review summarizes M₃-mAChR's expression patterns, functions, and underlying mechanisms of action in CVDs, especially in ischemia/reperfusion injury, cardiac hypertrophy, and heart failure, opening up a new research direction for the treatment of CVDs.

Keywords: cardiomyocyte; cardiovascular diseases; endothelial cell; fibroblast; muscarinic acetylcholine receptor M3.

Figure 1

Subclassification of muscarinic acetylcholine receptors and the downstream effectors. AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate; M₁, muscarinic acetylcholine receptor M₁; M₂, muscarinic acetylcholine receptor M₂; M₃: muscarinic acetylcholine receptor M₃; M₄, muscarinic acetylcholine receptor M₄; M₅, muscarinic acetylcholine receptor M₅; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

Figure 2

M₃-mAChR functions in the cardiac system through different cardiomyocytes. M₃-mAChR decreases Ca²⁺ overload, aiding in cytoprotection, enhancing cardiac function, activating delayed rectifier potassium current I_KM3 to regulate heart rate and repolarization, and interacting with the gap junction channel, Cx43, which may help coordinate repolarization rate in cardiomyocytes. M₃-mAChR may utilize several signaling pathways to generate various protective effects against cardiovascular diseases. AMPK, AMP-activated protein kinase; L-type Ca²⁺, L-type calcium; UPRmt, mitochondrial unfolded protein response; p38MAPK, p38 mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; miRNA, microRNA; BDNF, brain-derived neurophic factor; IL-1β, interleukin-1β; TGF-β1, transforming growth factor beta; HIF-1α, hypoxia-inducible factor 1; HO-1, heme oxygenase-1; VEGF, vascular endothelial growth factor; mTOR, mammalian target of the rapamycin; HSF1, heat shock transcription factor 1; SIRT3-AMPK, sirtuin 3/AMP-activated protein kinase; Nrf2, nuclear factor erythroid 2-related factor 2.