CLC chloride channels

Jentsch TJ, Friedrich T, Schriever A, Yamada H (1999) The Clc chloride channel family. Pflugers Arch 437 783-795... 

Brandt S, Jentsch TJ. 1995. C1C-6 and C1C-7 are two novel broadly expressed members of the CLC chloride channel family. FEBS Lett 377 15-20. 

PISEMA spectra of ion channel proteins (A) crystal structure and (B) simulated PISEMA spectrum of a 10.2 kDa KcsA monomer (97 residues), a K+ channel of S. lividans (PDB ID 1BL8) (C) crystal structure and (ID) simulated PISEMA spectrum of a monomeric 50.3 kDa (473 residues) CLC chloride channel from E. coli (PDB ID IKPK). 

Chloride channels are membrane proteins that allow for the passive flow of anions across biological membranes. As chloride is the most abundant anion under physiological conditions, these channels are often called chloride channels instead of anion channels, even though other anions (such as iodide or nitrate) may permeate better. As some CLC proteins function as CF-channels, whereas other perform CF/H+-exchangers are also mentioned here. 

There are nine different CLC isoforms in mammals. Based on homology, they can be classed into three branches. The first branch includes channels that reside predominantly in the plasma membrane. This includes C1C-1, a skeletal muscle chloride channel, C1C-2, a very broadly expressed channel, and CIC-Ka and CIC-Kb, which are expressed predominantly in the kidney but also in the ear. 

The intracellular negative electrical potential opposes chloride entry into cells. In the early proximal tubule the main cation, sodium, is predominantly reabsorbed concomitantly with bicarbonate so that the luminal chloride concentration actually increases. There are two main reabsorption mechanisms for chloride. The first is via an antipoiter in exchange for secretion of other anions (e.g., bicarbonate) or formate. The second occurs in the final two thirds of the proximal tubule. In the thick ascending limb of the loop of Henle, chloride is reabsorbed in association with sodium via NKCC2. The concentration gradient is maintained by a basolateral chloride pump, CLC-Kb (see Figure 45-7). A further chloride channel, CLC-5, is expressed at multiple sites in the nephron. ... 

Denfs disease is a familial renal tubular syndrome characterized by low molecular-weight proteinuria, hypercalciuria, nephrolithiasis and eventual renal failure. Mutations in the CLC-5 chloride channel are the basis for this disease. In humans, this channel is expressed mainly in the kidney, and mutations in the human CLCN5 promoter region might be the cause of Denf s disease (Devuyst et al. 1999, Hayama et al. 2000). 

Devuyst O, Christie PT, Courtoy PJ, Beauwens R and Thakker RV (1999) Intrarenal and subcel-lular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent s disease. Hum Mol Biol 8 247—257. 

Hayama a, Uchida S, Sasaki S and Marumo F (2000) Isolation and characterisation of the human CLC-5 chloride channel gene promoter. Gene 261 355-364. 

Gunther W, Luchow A, Cluzeaud F, Vandewalle A, Jentsch TJ. ClC-5, the chloride channel mutated in Dent s disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci USA 1998 95 8075-8080. 

Kornak U. Loss of the CLC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001 104 205-215. 

Modeling the Fast Gating Mechanism in the ClC-0 Chloride Channel. 

Liantonio, A. Pusch, M. PicoUo, A. Guida, P De Luca, A. Piemo, S. FracchioUa, G. Loiodice, F Tortorella, R Camerino, D. C. Investigations of pharmacologic properties of the renal CLC-Kl chloride channel co-expressed with barttin by the use of 2-(p-chlorophenoxy)propionic acid derivatives and other stmcturally unrelated chloride channels blockers. J. Am. Soc. Nephrol. 2004,15, 13-20. 

C1C-6 and C1C-7 define the third branch of the CLC family. These proteins are only about 45% identical to each other. Whereas CLC-7 is very broadly expressed, the CLC-6 protein seems to be restricted to the nervous system. It proved impossible to obtain plasma membrane chloride currents with either C1C-6 or C1C-7. This is due to the fact that both channels reside in intracellular organelles under most circumstances. Based on structural features, it appeals likely that they also mediate CF/H + exchange. 

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