NA-PROTEIN-INDEPENDENT MECHANISM( ACTIVATION OF THE MUSCARINIC K+ CHANNEL BY A G)

Muscarinic potassium channels (K-ACh) are composed of two subunits, GI RK1 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-modifed channels could in turn be gated by intracellular Na+, star ting at similar to 3 mM with an EC(50) of similar to 40 mM. The Na+-ga ting of K-ACh was operative both in native atrial cells and in a heter ologous system expressing recombinant channel subunits. Block of the N a+/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+ a ccumulation and in a manner indistinguishable from that of Na+-mediate d activation of the channel, suggesting that cardiac glycosides activa ted K-ACh by increasing intracellular Na+ levels. These results demons trate for the first time a direct effect of cardiac glycosides on atri al myocytes involving ion channels which are critical in the regulatio n of cardiac rhythm.