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

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Abstract
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. 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. 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. RS‐(±) CPP produced the same effect on rClC‐1 gating when added to the interior of the cell and in the extracellular solution. S‐(−) CPP modulates the gating of ClC‐1 to decrease the membrane Cl− conductance (GCl), which would account for the myotonic side effects of clofibrate and its derivatives. British Journal of Pharmacology (1999) 126, 1375–1382; doi:10.1038/sj.bjp.0702459