[1]¿p#1 newcommands Cardiac M3 Muscarinic Acetylcholine Receptor (M3-mAChR): A Context-Gated, Microdomain-Localized Stress-Response GPCR

Muscarinic acetylcholine receptors play a central role in cardiac autonomic regulation, yet the functional significance of the M 3 receptor subtype (M 3 ‑mAChR) in the heart has remained paradoxical. Activation of M 3 -mAChR has been linked to atrial arrhythmogenesis through shortening of action potential duration, while a large body of experimental evidence demonstrates robust cardioprotective effects of M 3 signaling in ischemia, hypertrophy, remodeling, and heart failure. Here, we synthesize three decades of work and advance a unifying conceptual framework in which cardiac M 3 -mAChR functions as a context‑gated, microdomain‑localized stress‑response G-protein‑coupled receptor. We propose that the apparent duality of M 3 signaling reflects integration of ligand source (neuronal acetylcholine versus choline), subcellular localization (intercalated disc versus diffuse sarcolemmal distribution), and myocardial disease state. Within this framework, M 3 -mAChR engages two partially separable signaling programs: a rapid electrical module mediated by a G q -coupled delayed rectifier K + current (I KM3 ), and a slower survival/remodeling module that limits Ca 2+ overload, preserves gap‑junction integrity, and activates cytoprotective kinase pathways. Recognition of M 3 -mAChR as a context‑dependent signaling hub reconciles previously conflicting observations and highlights new pharmacological opportunities, including biased agonism and microdomain‑selective modulation, for targeting cardiac muscarinic signaling in disease.