Paradoxical depolarization of Ba2+-treated muscle exposed to low extracellular K+: Insights into resting potential abnormalities in hypokalemic paralysis

Arie F. Struyk, Stephen C. Cannon

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

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 (VREST). 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, VREST became uncoupled from the K+ reversal potential and depolarized. Partial (∼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.

Original languageEnglish (US)
Pages (from-to)326-337
Number of pages12
JournalMuscle and Nerve
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2008

Keywords

  • Hypokalemic periodic paralysis
  • Inward rectifier potassium channels
  • Resting membrane potential

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)

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