Modulation Of Cardiac Inward-Rectifier K+ Current IK1 By Intracellular K+ And Extracellular K+

Abstract

The inwardly-rectifying K+ current (IK1) is important for heart cell function because it sets the resting potential, influences cell excitability, and promotes repolarization of the action potential. My objective was to investigate the modulation of IK1 by extracellular K+ (K+o) and intracellular K+ (K+i). IK1 was recorded from whole-cell-configured guinea-pig ventricular myocytes that were dialyzed with Na+-free EGTA-buffered pipette-filling solution and bathed with Na+ or NMDG+ solution that contained agents that inhibit non-IK1 currents. Lowering K+o from standard 5.4 to 2 and 1 mM shifted the reversal potential (Erev) of IK1 in accord with calculated K+ equilibrium potential (EK), and altered IK1 amplitude in accord with conductance (GK1)? ?K+o. Surprisingly, myocytes bathed with 0-mM K+ solution had a small outward IK1 at holding potential (Vhold) ?85 mV. This IK1 was attributed to channel-activation by T-tubular K+ (K+T) whose concentration is sensitive to the flow of T-tubular IK1. K+T in myocytes bathed with 0-mM K+ solution was ? 3.2 mM at Vhold ?85 mV, but ? 0.3 mM following large K+T-depleting flows of inward IK1 at ?160 mV. Results consistent with interplay of IK1 and K+T were also obtained in experiments on myocytes bathed with 2-, 5.4-, and 15-mM K+ solution. Myocytes were dialyzed with pipette solutions that contained 0-140 mM K+ to investigate modulation by K+i. When IK1 at Vhold was kept small, Erev varied with pipette K+ in a near-Nernstian manner (i.e., Erev ? EK); however, when IK1 (Vhold) was large and inward, Erev was markedly negative to nominal EK. Findings in experiments that involved shifting Vhold, changing K+o, and application of Ba2+ and Cs+ suggest that the magnitude/direction of IK1 strongly affects the concentration of K+ in submembrane cytoplasm. Classical GK1-voltage parameters GK1max and V0.5 (but not slope factor) were affected by decreases in K+i: GK1max declined by ? 25% per decade decrease in K+i, and V0.5 shifted approximately as 0.5 ? EK-shift. The latter findings are discussed and compared with those of earlier studies on the dependence of inwardly-rectifying K+ conductance on K+i.