4-chloro-m-cresol, a potent and specific activator of the skeletal muscle ryanodine receptor

Annegret Herrmann-Frank, Michael Richter, Sandor Sarközi, Ursula Mohr, Frank Lehmann-Horn

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

The aim of the present study was to determine the effects of 4-chloro-m-cresol (4-CmC), a preservative often added to drugs intravenously administered, on the skeletal muscle sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor. In heavy SR vesicles obtained from rabbit back muscles, 4-CmC stimulated Ca2+-activated [3H]ryanodine binding with an EC50 of about 100 μM. In the same concentration range, 4-CmC directly activated the isolated Ca2+ release channel reconstituted into planar lipid bilayers. The sensitivity to 4-CmC was found to be higher when applied to the luminal side of the channel suggesting binding site(s) different from those of nucleotides and caffeine. In skeletal muscle fibre bundles obtained from biopsies of patients susceptible to malignant hyperthermia, a skeletal muscle disease caused by point mutations in the ryanodine receptor, 4-CmC evoked caffeine-like contractures. Contrary to caffeine which induces contractures in millimolar concentrations, the threshold concentration for 4-CmC was 25 μM compared to 75 μM for non-mutated control fibres. Since these data strongly indicate that 4-CmC specifically activates SR Ca2+ release also in intact cell systems, this substance might become a powerful tool to investigate ryanodine receptor-mediated Ca2+ release in muscle and non-muscle tissue.

Original languageEnglish
Pages (from-to)31-40
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1289
Issue number1
DOIs
Publication statusPublished - Feb 9 1996

Keywords

  • Caffeine
  • Calcium channel
  • Malignant hyperthermia
  • Ryanodine receptor
  • Sarcoplasmic reticulum
  • Skeletal muscle

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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