Paradoxical depolarization of BA2+- treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis.
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.
Struyk
Arie F
AF
Department of Neurology, University of Texas Southwestern Medical Center, 6001 Forest Park Avenue, ND4.214B, Dallas, TX 75390-8813, USA. arie.struyk@utsouthwestern.edu
Cannon
Stephen C
SC
D000818:Animals; D001464:Barium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004553:Electric Conductivity; D045604:Extracellular Fluid / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology
D001464:Barium; D011188:Potassium