The voltage-sensitive cardiac M2 muscarinic receptor modulates the inward rectification of the G protein-coupled, ACh-gated K+ current.

The acetylcholine (ACh)-gated inwardly rectifying K⁺ current (I_KACh) plays a vital role in cardiac excitability by regulating heart rate variability and vulnerability to atrial arrhythmias. These crucial physiological contributions are determined principally by the inwardly rectifying nature of I_KACh. Here, we investigated the relative contribution of two distinct mechanisms of I_KACh inward rectification measured in atrial myocytes: a rapid component due to K_ACh channel block by intracellular Mg²⁺ and polyamines; and a time- and concentration-dependent mechanism. The time- and ACh concentration-dependent inward rectification component was eliminated when I_KACh was activated by GTPγS, a compound that bypasses the muscarinic-2 receptor (M₂R) and directly stimulates trimeric G proteins to open K_ACh channels. Moreover, the time-dependent component of I_KACh inward rectification was also eliminated at ACh concentrations that saturate the receptor. These observations indicate that the time- and concentration-dependent rectification mechanism is an intrinsic property of the receptor, M₂R; consistent with our previous work demonstrating that voltage-dependent conformational changes in the M₂R alter the receptor affinity for ACh. Our analysis of the initial and time-dependent components of I_KACh indicate that rapid Mg²⁺-polyamine block accounts for 60-70% of inward rectification, with M₂R voltage sensitivity contributing 30-40% at sub-saturating ACh concentrations. Thus, while both inward rectification mechanisms are extrinsic to the K_ACh channel, to our knowledge, this is the first description of extrinsic inward rectification of ionic current attributable to an intrinsic voltage-sensitive property of a G protein-coupled receptor. [ABSTRACT FROM AUTHOR]