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1 Pediatrics, Univ. of Iowa, Iowa City, Iowa, United States
2 Pediatrics, University of Iowa Hospital & Clinics, Iowa City, Iowa, United States
* To whom correspondence should be addressed. E-mail: fred-lamb{at}uiowa.edu.
ClC-3 is a member of the ClC family of anion channels/transporters. Recently, the closely-related proteins ClC-4 and ClC-5 were shown to be Cl-/H+ antiporters (39, 44). The function of ClC-3 has been controversial. We studied anion currents in HEK293T cells expressing wild-type or mutant ClC-3. The basic biophysical properties of ClC-3 currents were very similar to those of ClC-4 and ClC-5, and distinct from those of the swelling-activated anion channel (IClswell). ClC-3 expression induced currents with time-dependent activation that rectified sharply in the outward direction. The reversal potential of the current shifted by -48.3 ± 2.5 mV per 10-fold (decade) change in extracellular Cl- concentration, which did not conform to the behavior of an anion-selective channel based upon the Nernst equation, which predicts a -58.4 mV/decade shift at 22°C. Manipulation of extracellular pH (6.35 to 8.2) altered reversal potential by 10.2 ± 3.0 mV/decade suggesting that ClC-3 currents were coupled to proton movement. Mutation of a specific glutamate residue (E224A) changed voltage-dependence in a manner similar to that observed in other ClC Cl-/H+ antiporters. Mutant currents exhibited Nernstian changes in reversal potential in response to altered extracellular Cl- concentration that averaged -60 ± 3.4 mV per decade, and were pH-independent. Thus, ClC-3 overexpression induced a pH-sensitive conductance in HEK293T cells that is biophysically similar to ClC-4 and ClC-5.
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