Channel or transporter? The CLC saga continues


Corresponding author Michael Pusch: Istituto di biofisica, CNR, Via De Marini 6, I-16149 Genova, Italy. Email:


It was recently shown that the putative bacterial Cl channel, ClC-ec1, is in reality a Cl–H+ antiporter. Our group has now shown that this is also the case for two human CLCs, ClC-4 and ClC-5. We found that the flux of Cl in one direction is stoichiometrically coupled to the movement of protons in the opposite direction, unveiling a behaviour that is typical of a transporter rather than a channel. This discovery will surely stimulate further research to elucidate the molecular elements responsible for the behaviour as a transporter. On the physiological level, the antiport activity of ClC-4/ClC-5 must lead to a review of the role of CLC proteins in intracellular compartments. Small organic molecules have been extremely useful tools for studying ion channels and many commercial drugs target specific ion channel proteins. Several blockers have been found to inhibit the plasma membrane-localized CLC channels ClC-0, ClC-1 and ClC-Ka. These compounds include 9-anthracene-carboxylic acid (9-AC), p-chlorophenoxy-propionic acid (CPP) and its derivatives, and 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS). Two different binding sites have been identified, one extracellular and one intracellular. However, high-affinity ligands for most CLC proteins are still missing. Apart from being useful biophysical tools, such drugs may provide a way to modulate protein function in vivo. With these tasks to be accomplished, it is definitely an exciting time in the chloride transport field.