Electrophysiological Characterization of Cardiac Muscarinic Acetylcholine Receptors: Different Subtypes Mediate Different Potassium Currents

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Abstract
To characterize electrophysiologically the K+ currents mediated by various mAChR subtypes, we performed detailed whole-cell patch-clamp studies in canine atrial myocytes. IKACh was induced by 1 mM ACh (acetylcholine) or by arecaidine but-2-ynyl ester tosylate (100 nM, an M2 receptor selective agonist) and was blocked by methoctramine (20 nM, an M2 receptor selective antagonist). Tetramethylammonium (0.5 mM) activated a K+ conductance with delayed rectifying properties (IKM3) and the currents were highly sensitive to 4-diphenylacetoxy-N-methylpiperidine methiodide (2 nM, an M3 receptor inhibitor). 4-aminopyridine (1 mM) induced a delayed rectifier-like current (IK4AP) which was selectively suppressed by tropicamide (200 nM, an M4 receptor blocker). The current waveforms, I-V relationships, steady-state voltage-dependence, kinetics and pharmacological properties of these three currents were different from one another and distinct from the classical delayed rectifier K+ currents (IKr and IKs). Both IKACh and IK4AP were sensitive to pertussis ntoxin, whereas IKM3 was not. Isoproterenol (1 mM) markedly depressed IKM3, but increased IK4AP and did not alter IKACh. The effects of isoproterenol were reversed by propranolol (1 mM); and ACh completely suppressed IKM3 and IK4AP. The results suggest that the K+ currents mediated by different subtypes of mAChR represent different populations of K+ channels and that the cholinergic regulation of the heart’s electrical function is a consequence of activating multiple mAChRs linked to different effector systems with potentially varying signal transduction.

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