CLCN1/2/KA/KB transport cytosolic Cl- to extracellular region

Stable Identifier
Reaction [transition]
Homo sapiens
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Chloride channel proteins 1, 2, Ka and Kb (CLCN1, 2, KA, KB) can mediate Cl- influx across the plasma membrane of almost all cells. CLCN1 is expressed mainly on skeletal muscle where it is involved in the electrical stability of the muscle. CLCN1 is thought to function in a homotetrameric form (Steimeyer et al. 1994). CLCN2 is ubiquitously expressed, playing a role in the regulation of cell volume (Cid et al. 1995, Niemeyer et al. 2009). Defects in CLCN1 cause myotonia congenita, an autosomal dominant disease (MCD aka Thomsen disease, MIM:160800). It is characterized by muscle stiffness due to delayed relaxation, resulting from membrane hyperexcitability (Meyer-Kleine et al. 1995, Steimeyer et al. 1994). Defects in CLCN1 also cause autosomal recessive myotonia congenita (MCR aka Becker disease, MIM:255700) (Koch et al. 1992, Meyer-Kleine et al. 1995), a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Becker disease is more common and more severe than Thomsen disease.

CLCNKA and B (Kieferle et al. 1994) are predominantly expressed in distal nephron segments of the kidney (Takeuchi et al. 1995) and the inner ear (Estevez et al. 2001, Schlingmann et al. 2004). They are tightly associated with their essential beta subunit barttin (BSND), requiring it to be fully functional channels (Fischer et al. 2010, Scholl et al. 2006). These channels bound to BSND are essential for renal Cl- reabsorption (Waldegger & Jentsch 2000) and K+ recycling in the inner ear (Estevez et al. 2001). Defects in CLCNKA and B cause Bartter syndrome type 4B (BS4B; MIM:613090) characterized by impaired salt reabsorption and sensorineural deafness (Schlingmann et al. 2004, Nozu et al. 2008). Defects in BSND cause Bartter syndrome type 4A (BS4A aka infantile Bartter syndrome with sensorineural deafness; MIM:602522) characterized by impaired salt reabsorption in the thick ascending loop of Henle and sensorineural deafness (Birkenhager et al. 2001, Nozu et al. 2008).
Literature References
PubMed ID Title Journal Year
20538786 Barttin activates ClC-K channel function by modulating gating

Janssen, AG, Fischer, M, Fahlke, C

J. Am. Soc. Nephrol. 2010
8041726 Two highly homologous members of the ClC chloride channel family in both rat and human kidney

Bens, M, Fong, P, Jentsch, TJ, Kieferle, S, Vandewalle, A

Proc. Natl. Acad. Sci. U.S.A. 1994
8544406 Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney

Marumo, F, Takeuchi, Y, Uchida, S, Sasaki, S

Kidney Int. 1995
18310267 Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness

Kaito, H, Nakanishi, K, Igarashi, T, Fu, XJ, Iijima, K, Kanda, K, Nozu, Y, Inagaki, T, Matsuo, M, Nozu, K, Yoshikawa, N, Sekine, T

J. Med. Genet. 2008
11734858 Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion

Stein, V, Hildebrandt, F, Boettger, T, Jentsch, TJ, Otto, E, Estévez, R, Birkenhäger, R

Nature 2001
8533761 Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia

Ricker, K, Jentsch, TJ, Steinmeyer, K, Meyer-Kleine, C, Koch, MC

Am. J. Hum. Genet. 1995
19153159 Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons

Cid, LP, Sepúlveda, FV, Briones, R, Niemeyer, MI, Yusef, YR

J. Physiol. (Lond.) 2009
16849430 Barttin modulates trafficking and function of ClC-K channels

Scholl, U, Janssen, AG, Müller-Newen, G, Alekov, A, Hebeisen, S, Fahlke, C

Proc. Natl. Acad. Sci. U.S.A. 2006
7795595 Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues

Montrose-Rafizadeh, C, Cid, LP, Cutting, GR, Guggino, WB, Smith, DI

Hum. Mol. Genet. 1995
8112288 Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen)

Jentsch, TJ, Pusch, M, Steinmeyer, K, Lorenz, C, Koch, MC

EMBO J. 1994
15044642 Salt wasting and deafness resulting from mutations in two chloride channels

Seyberth, HW, Waldegger, S, Holder, M, Reinalter, SC, Waldegger, P, Konrad, M, Schlingmann, KP, Jeck, N

N. Engl. J. Med. 2004
10831588 Functional and structural analysis of ClC-K chloride channels involved in renal disease

Jentsch, TJ, Waldegger, S

J. Biol. Chem. 2000
11687798 Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure

Kispert, A, Ruf, EM, Vollmer, M, Jeck, N, Maier-Lutz, I, Konrad, M, Otto, E, Milford, DV, Birkenhäger, R, Sudbrak, R, Landau, D, Antignac, C, Hildebrandt, F, Feldmann, D, Omran, H, Beekmann, F, Knoers, NV, Fekete, A, Schürmann, MJ

Nat. Genet. 2001
1379744 The skeletal muscle chloride channel in dominant and recessive human myotonia

Ricker, K, Lehmann-Horn, F, Zoll, B, Jentsch, TJ, Otto, M, Steinmeyer, K, Grzeschik, KH, Lorenz, C, Wolf, F, Koch, MC

Science 1992
Catalyst Activity

voltage-gated chloride channel activity of CLCN1/2/KA/KB [plasma membrane]

Orthologous Events
Cross References
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