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

E C Aromataris1, D S Astill, G Y Rychkov

  • 1Department of Physiology, University of Adelaide, South Australia, Australia.

British Journal of Pharmacology
|April 27, 1999
PubMed

Insights

The S-(-) enantiomer of RS-(+/-) 2-(4-chlorophenoxy)propionic acid (CPP) alters rat skeletal muscle chloride channel 1 (rCIC-1) gating, decreasing chloride conductance and explaining myotonic side effects of clofibrate derivatives.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biophysics

Background:

  • Myotonic side effects are associated with clofibrate derivatives.
  • The cellular mechanisms underlying these side effects require elucidation.

Purpose of the Study:

  • To investigate the mechanism by which clofibrate derivatives cause myotonic side effects.
  • To examine the effects of RS-(+/-) 2-(4-chlorophenoxy)propionic acid (CPP) and its enantiomers on the rat skeletal muscle chloride channel rCIC-1.

Main Methods:

  • Whole-cell patch-clamping technique was employed.
  • Sf-9 cells expressing the rat skeletal muscle chloride channel, rCIC-1, were utilized.
  • The effects of RS-(+/-) CPP and its S-(-) enantiomer on rCIC-1 gating kinetics and voltage dependence were analyzed.

Main Results:

  • The S-(-) enantiomer of CPP significantly altered rCIC-1 gating, causing faster deactivation at hyperpolarizing potentials.
  • Both RS-(+/-) CPP and S-(-) CPP induced a concentration-dependent shift in voltage dependence, with S-(-) CPP being more potent (EC50 = 0.21 mM).
  • The R-(+) enantiomer had no effect, and RS-(+/-) CPP did not block Cl- passage, indicating a modulatory effect on gating.

Conclusions:

  • S-(-) CPP decreases the affinity of the Cl- binding site within the rCIC-1 channel, altering its gating.
  • This modulation reduces membrane chloride conductance (GCl), explaining the myotonic side effects observed with clofibrate derivatives.

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