CLC chloride channels and transporters - from biophysics to human genetic diseases

Michael Pusch
Istituto di Biofisica, Genova


Chloride transporting proteins play fundamental roles in many tissues in the plasma membrane as well as in intracellular membranes. They have received increasing attention in the last years because crucial, and often unexpected and novel physiological functions have been disclosed using gene-targeting approaches, X-ray crystallography and biophysical analysis. CLC proteins form a gene-family that comprises nine members in mammals, at least seven of which are involved in human genetic diseases. The X-ray structure of bacterial and algal CLC homologues revealed a complex fold, and confirmed the anticipated, homodimeric double-barreled architecture of CLC-proteins with two separate Cl- ion transport pathways, one in each subunit. Four of the mammalian CLC proteins, ClC-1, ClC-2, ClC-Ka, and ClC-Kb, are Cl- ion channels that fulfill their functional roles - stabilization of the membrane potential, transepithelial salt transport, and ion homeostasis - in the plasma membrane. The other five CLC proteins are predominantly expressed in intracellular organelles, like endosomes and lysosomes, where they are probably important for a proper luminal acidification, in concert with the V-type H+-ATPase. All intracellular CLCs are secondary active Cl-/H+ antiporters. The seminar will concentrate on the CLC-2 channel and its novel glial subunit GlialCAM, which are involved in white matter edema, and the endosomal CLC-5 exchanger, which is mutated in Dent disease, a nephropathy associated with kidney stones.