Single Channel Studies of Inward Rectifier Potassium Channel Regulation by Muscarinic Acetylcholine Receptors

Negative regulation of the heartbeat rate involves the activation of an inwardly rectifying potassium current (I_KACh) by G protein–coupled receptors such as the m2 muscarinic acetylcholine receptor. Recent studies have shown that this process involves the direct binding of G_βγ subunits to the NH₂- and COOH-terminal cytoplasmic domains of the proteins termed GIRK1 and GIRK4 (Kir3.1 and Kir3.4/CIR), which mediate I_KACh. Because of the very low basal activity of native I_KACh, it has been difficult to determine the single channel effect of G_βγ subunit binding on I_KACh activity. Through analysis of a novel G protein–activated chimeric inward rectifier channel that displays increased basal activity relative to I_KACh, we find that single channel activation can be explained by a G protein–dependent shift in the equilibrium of open channel transitions in favor of a bursting state of channel activity over a long-lived closed state.