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

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

Stable Identifier

R-HSA-2744228

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, extracellular region, plasma membrane

ReviewStatus

5/5

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

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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