Different effects of mexiletine on two mutant sodium channels causing paramyotonia congenita and hyperkalemic periodic paralysis

K. Weckbecker, A. Würz, B. Mohammadi, T. Mansuroglu, A. L. George, H. Lerche, R. Dengler, F. Lehmann-Horn, N. Mitrovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Effects of the antiarrhythmic and antimyotonic drug mexiletine were studied on two sodium channel mutants causing paramyotonia congenita (R1448H) and an overlap paramyotonic and hyperkalemic paralytic syndrome (M1360V). Channels were expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. Compared to the wild-type, channel, both mutants showed alterations of inactivation, i.e. slower inactivation, left shift of steady-state inactivation and faster recovery from inactivation. Mexiletine caused a significantly larger use-dependent block of the R1448H mutant when compared to M1360V and wild-type channels. This can be explained by a prolonged recovery from mexiletine block as observed for R1448H channels, since the affinity of mexiletine for the inactivated state was similar for all three clones. The use-dependent block of sodium channels by mexiletine reduces repetitive series of action potentials and therefore improves muscle stiffness in myotonic patients. The enhanced use-dependent block as seen with R1448H may explain the extraordinary therapeutic efficacy of mexiletine in most patients with paramyotonia congenita. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)31-39
Number of pages9
JournalNeuromuscular Disorders
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2000

Keywords

  • Channelopathies
  • Local anaesthetics
  • Myotonia
  • Patch-clamp

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

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