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

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 EC 50 of 0.79 and 0.21 m M 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 EC 50 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 (G Cl ), 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