Na⁺ activation of the muscarinic K⁺ channel by a G-protein-independent mechanism

Muscarinic potassium channels (K(ACh)) are composed of two subunits, GIRK1 and GIRK4 (or CIR), and are directly gated by G proteins. We have identified a novel gating mechanism of K(ACh), independent of G-protein activation. This mechanism involved functional modification of K(ACh) which required hydrolysis of physiological levels of intracellular ATP and was manifested by an increase in the channel mean open time. The ATP-modified channels could in turn be gated by intracellular Na⁺, starting at ~3 mM with an EC₅₀ of ~40 mM. The Na⁺-gating of K(ACh) was operative both in native atrial cells and in a heterologous system expressing recombinant channel subunits. Block of the Na⁺/K⁺ pump (e.g., by cardiac glycosides) caused significant activation of K(ACh) in atrial cells, with a time course similar to that of Na⁺ accumulation and in a manner indistinguishable from that of Na⁺-mediated activation of the channel, suggesting that cardiac glycosides activated K(Ach) by increasing intracellular Na⁺ levels. These results demonstrate for the first time a direct effect of cardiac glycosides on atrial myocytes involving ion channels which are critical in the regulation of cardiac rhythm.