A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties

Jonathan Satin, John W. Kyle, Michael Chen, Peter Bell, Leanne L. Cribbs, Harry A. Fozzard, Richard B. Rogart

Research output: Contribution to journalArticlepeer-review

333 Scopus citations

Abstract

The cardiac sodium channel α subunit (RHI) is less sensitive to tetrodotoxln (TTX) and saxitoxin (STX) and more sensitive to cadmium than brain and skeletal muscle (μl) isoforms. An RHI mutant, with Tyr substituted for Cys at position 374 (as in μl) confers three properties of TTX-sensitive channels: (i) greater sensitivity to TTX (730-fold); (ii) lower sensitivity to cadmium (28-fold); and (iii) altered additional block by toxin upon repetitive stimulation. Thus, the primary determinant of high-affinity TTX-STX binding is a critical aromatic residue at position 374, and the interaction may take place possibly through an ionized hydrogen bond. This finding requires revision of the sodium channel pore structure that has been previously suggested by homology with the potassium channel.

Original languageEnglish
Pages (from-to)1202-1205
Number of pages4
JournalScience
Volume256
Issue number5060
DOIs
StatePublished - 1992

ASJC Scopus subject areas

  • General

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