Choline Modulates Cardiac Membrane Repolarization by Activating an M3 Muscarinic Receptor and its Coupled K+ Channel

Abstract

Choline is a necessary substrate of the lipid membrane and for acetylcholine synthesis. Accumulating evidence indicates that besides being a structural component, choline is also a functional modulator of the membrane. It has been shown to be a muscarinic acetylcholine receptor (mAChR) agonist and can induce a novel K+ current in cardiac cells. However, the potential role of choline in modulating cardiac functions remained unstudied despite that mAChRs are known to be important in regulating heart functions. With microelectrode techniques, we found that choline produced concentration-dependent (0.1 approximately 10 mm) decreases in sinus rhythm and action potential duration in isolated guinea pig atria. The effects were reversed by 2 nm 4DAMP (an M3-selective antagonist). Whole-cell patch-clamp recordings in dispersed myocytes from guinea pig and canine atria revealed that choline is able to induce a K+ current with delayed rectifying properties. The choline-induced current was suppressed by low concentrations of 4DAMP (2 approximately 10 nm). Antagonists toward other subtypes (M1, M2 or M4) all failed to alter the current. The affinity of choline (Kd) at mAChRs derived from displacement binding of [3H]-NMS in the homogenates from dog atria was 0.9 mm, consistent with the concentration needed for the current induction and for the HR and APD modulation. Our data indicate that choline modulates the cellular electrical properties of the hearts, likely by activating a K+ current via stimulation of M3 receptors.

Altered Cardiovascular Responses in Mice Lacking the M1Muscarinic Acetylcholine Receptor

“…These studies suggest that the M 1 or M 4 mAChR may be involved in the regulation of the heart. More recently, RT-PCR analysis has shown the expression of the M 1 mAChR subtype in rat and guinea pig ventricular cells (Gallo et al, 1993;Sharma et al, 1996) and the M 3 and M 4 mAChR subtypes in dog atrial cells (Shi et al, 1999b).…”

Pharmacological Conversion of a Cardiac Inward Rectifier into an Outward Rectifier Potassium Channel

“…The current evoked by choline, tetramethylammonium, and the muscarinic agonist pilocarpine (Pilo) was proposed to be mediated by the M 3 muscarinic receptor, and the current was named I KM3 (Shi et al, 1999a(Shi et al, ,b, 2003Wang et al, 1999Wang et al, , 2004. This group postulated that I KM3 modulates cardiac electrical activity (Shi et al, 1999b;Wang et al, 1999) and plays a role in the pathophysiology of atrial fibrillation (Yeh et al, 2007) and cytoprotection against myocardial injuries (Yang et al, 2005). Despite the prediction of a novel channel, the molecular correlates of the K 1 channel subunits that underlie I KM3 remained elusive (Yang and Nerbonne, 2016).…”

Atrial tachycardia induces remodelling of muscarinic receptors and their coupled potassium currents in canine left atrial and pulmonary vein cardiomyocytes

“…Representative I KM3 recordings are illustrated in Figure 3a. The current showed typical rapid activation and timedependent relaxation with large tail currents on repolarization (Shi et al, 1999a(Shi et al, , b, c, 2003Wang et al, 2001). The currents were reduced in cells from tachypaced dogs.…”

“…Intact M 2 receptor-coupled K þ -channel subunits are essential for cholinergic AF in animal models (Kovoor et al, 2001). In addition to the well-known presence of the M 2 receptor and its corresponding K þ -current (which we will refer to as I KM2 (M 2 receptor-mediated inward rectifier K þ currents)) in mammalian hearts, recent studies indicate the presence in atrial myocytes of various other mAChR subtypes coupled to distinct K þ -currents: I KM3 (M 3 receptor-mediated inward rectifier K þ currents) coupled to the M 3 receptor, typically activated by choline and I KM4 (M 4 receptor-mediated inward rectifier K þ currents) coupled to the M 4 receptor, typically activated by 4-aminopyridine, 4AP (Navarro-Polanco and Sanchez-Chapula, 1997; Shi et al, 1999aShi et al, , b, c, 2003Wang et al, 1999Wang et al, , 2001Wang et al, , 2004. The very rapid atrial firing caused by AF is known to remodel atrial electrical properties in a way that promotes AF occurrence and maintenance (Wijffels et al, 1995).…”