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(beta gamma) 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 deter mine the single channel effect of G(beta gamma) 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.