The combination of sarcolemmal depolarization and hypokalemia exhibited by the different forms of hypokalemic paralysis has been attributed to abnormalities of the K+ conductance governing the resting membrane potential (V(REST)). Supportive data have been observed in muscle fibers biopsied from patients with familial hypokalemic periodic paralysis (HypoPP) that paradoxically depolarize at low K+. Although this observation is consistent with anomalous K+ conductance, rigorous experimental support is lacking. To establish a foundation for understanding the pathophysiology of hypokalemic paralysis, we studied Ba2+-treated muscle fibers under voltage clamp. As anticipated, Ba2+ blocked inward rectifying K+ (IRK) currents, and thereby promoted depolarization, supporting the notion that the IRK conductance governs V(REST). The IRK conductance also declined when muscle was challenged with reduced external K+. When the external K+ declined below 1 mM, V(REST) became uncoupled from the K+ reversal potential and depolarized. Partial ( approximately 50%) block of the IRK conductance with Ba2+ potentiated this uncoupling threshold, such that depolarization could be elicited by exposure to 2 mM external K+. A quantitative computer model of resting ionic conductances was constructed, and simulations demonstrated that small alterations to resting conductances, such as adding a low-amplitude aberrant inward current flowing through "gating pores" in mutant Na+ channels causing HypoPP-2, can promote paradoxical depolarization in low K+. These findings offer a simple explanation for some of the heretofore poorly understood physiological abnormalities of HypoPP muscle and support the notion that pathological gating pore leakage currents may directly predispose to paralytic attacks.