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Sodium channel in human malignant hyperthermia

J E Fletcher1, S J Wieland, S M Karan

  • 1Department of Anesthesiology, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19102-1192, USA.

Anesthesiology
|May 1, 1997
PubMed
Summary

Malignant hyperthermia susceptibility is linked to reduced SkM2 sodium channel expression in muscle tissue. This finding, observed in patient biopsies, suggests SkM2 down-regulation may be a common pathway in this genetic disorder.

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Altered expression of the SkM2 sodium channel subunit was previously observed in cell cultures from individuals susceptible to malignant hyperthermia (MH).
  • The relevance of these in vitro findings to in vivo MH pathophysiology remained unclear.

Purpose of the Study:

  • To investigate whether the observed alterations in SkM2 sodium channel subunit expression are artifacts of cell culture or are genuinely associated with malignant hyperthermia.
  • To determine the in vivo relevance of SkM2 sodium channel alterations in individuals susceptible to MH.

Main Methods:

  • mRNA analysis was employed to quantify SkM2 transcript levels in muscle biopsies.
  • Functional SkM2 protein expression was assessed by measuring tetrodotoxin sensitivity of muscle twitches in vastus lateralis biopsy samples.

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Main Results:

  • SkM2 transcript levels were significantly depressed (115-fold) in 71% of MH-susceptible individuals.
  • Functional SkM2 protein expression, indicated by tetrodotoxin sensitivity, was decreased by at least fourfold in MH-susceptible individuals compared to controls.

Conclusions:

  • Down-regulation of SkM2 mRNA and/or functional protein expression was confirmed in muscle biopsies from MH-susceptible individuals.
  • These findings suggest that SkM2 down-regulation may represent a common pathway in the pathophysiology of malignant hyperthermia, irrespective of the specific causative mutation.
  • MH is a genetically heterogeneous disorder, and SkM2 alterations could be a unifying factor in susceptibility.