Received September 9, 2005
Revised September 19, 2005
Accepted after revision September 20, 2005

¹ CNR

^* To whom correspondence should be addressed. E-mail: pusch{at}ge.ibf.cnr.it.

	Abstract

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 CLC's, 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 behavior 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 behavior 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 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'-disulfonic 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.

Key Words: Chloride channel, Ion transport, pH