Modulation of the gating of ClC-1 by S-(-) 2-(4-chlorophenoxy)propionic acid

E. C. Aromataris, D. St J. Astill, G. Y. Rychkov, S. H. Bryant, A. H. Bretag, M. L. Roberts

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37 Citations (Scopus)


1. Using whole-cell patch-clamping and Sf-9 cells expressing the rat skeletal muscle chloride channel, rClC-1, the cellular mechanism responsible for the myotonic side effects of clofibrate derivatives was examined. 2. RS-(±) 2-(4-chlorophenoxy)propionic acid (RS-(±) CPP) and its S-(-) enantiomer produced pronounced effects on ClC-1 gating. Both compounds caused the channels to deactivate more rapidly at hyperpolarizing potentials, which showed as a decrease in the time constants of both the fast and slow deactivating components of the whole cell currents. Both compounds also produced a concentration-dependent shift in the voltage dependence of channel apparent open probability to more depolarizing potentials, with an EC50 of 0.79 and 0.21 mM for the racemate and S-(-) enantiomer respectively. R-(+) CPP at similar concentrations had no effect on gating. RS-(±) CPP did not block the passage of Cl- through the pore of rClC-1. 3. ClC-1 is gated by Cl- binding to a site within an access channel and S-(-) CPP alters gating of the channel by decreasing the affinity of this binding site for Cl-. Comparison of the EC50 for RS-(±) CPP and S-(-) CPP indicates that R-(+) CPP can compete with the S-(-) enantiomer for the site but that it is without biological activity. 4. RS-(±) CPP produced the same effect on rClC-1 gating when added to the interior of the cell and in the extracellular solution. 5. S-(-) CPP modulates the gating of ClC-1 to decrease the membrane Cl- conductance (G(Cl)), which would account for the myotonic side effects of clofibrate and its derivatives.

Original languageEnglish
Pages (from-to)1375-1382
Number of pages8
JournalBritish Journal of Pharmacology
Issue number6
Publication statusPublished or Issued - 1999
Externally publishedYes


  • 2-(4-Chlorophenoxy)propionic acid
  • Chloride channels
  • ClC-1
  • Myotonia
  • Skeletal muscle
  • Whole-cell patch-clamp

ASJC Scopus subject areas

  • Pharmacology

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