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Structural highlights

Disease

CLCN2_HUMAN Familial hyperaldosteronism type II;Leukoencephalopathy with mild cerebellar ataxia and white matter edema;Juvenile myoclonic epilepsy. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

CLCN2_HUMAN Voltage-gated and osmosensitive chloride channel. Forms a homodimeric channel where each subunit has its own ion conduction pathway. Conducts double-barreled currents controlled by two types of gates, two fast glutamate gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Displays inward rectification currents activated upon membrane hyperpolarization and extracellular hypotonicity (PubMed:16155254, PubMed:17567819, PubMed:19191339, PubMed:23632988, PubMed:29403011, PubMed:29403012, PubMed:36964785, PubMed:38345841). Contributes to chloride conductance involved in neuron excitability. In hippocampal neurons, generates a significant part of resting membrane conductance and provides an additional chloride efflux pathway to prevent chloride accumulation in dendrites upon GABA receptor activation. In glia, associates with the auxiliary subunit HEPACAM/GlialCAM at astrocytic processes and myelinated fiber tracts where it may regulate transcellular chloride flux buffering extracellular chloride and potassium concentrations (PubMed:19191339, PubMed:22405205, PubMed:23707145). Regulates aldosterone production in adrenal glands. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated calcium channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis (PubMed:29403011, PubMed:29403012). Contributes to chloride conductance in retinal pigment epithelium involved in phagocytosis of shed photoreceptor outer segments and photoreceptor renewal (PubMed:36964785). Conducts chloride currents at the basolateral membrane of epithelial cells with a role in chloride reabsorption rather than secretion (By similarity) (PubMed:16155254). Permeable to small monovalent anions with chloride > thiocyanate > bromide > nitrate > iodide ion selectivity (By similarity) (PubMed:29403012).[UniProtKB:P35525][UniProtKB:Q9R0A1]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]}

References

1. ↑ Peña-Münzenmayer G, Catalán M, Cornejo I, Figueroa CD, Melvin JE, Niemeyer MI, Cid LP, Sepúlveda FV. Basolateral localization of native ClC-2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS-2 domain di-leucine motif. J Cell Sci. 2005 Sep 15;118(Pt 18):4243-52. PMID:16155254 doi:10.1242/jcs.02525
2. ↑ Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, Jentsch TJ. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci. 2007 Jun 13;27(24):6581-9. PMID:17567819 doi:10.1523/JNEUROSCI.0338-07.2007
3. ↑ Saint-Martin C, Gauvain G, Teodorescu G, Gourfinkel-An I, Fedirko E, Weber YG, Maljevic S, Ernst JP, Garcia-Olivares J, Fahlke C, Nabbout R, LeGuern E, Lerche H, Poncer JC, Depienne C. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum Mutat. 2009 Mar;30(3):397-405. PMID:19191339 doi:10.1002/humu.20876
4. ↑ Jeworutzki E, López-Hernández T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Müller CS, Schulte U, Nunes V, Martínez A, Jentsch TJ, Gasull X, Pusch M, Estévez R. GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron. 2012 Mar 8;73(5):951-61. PMID:22405205 doi:10.1016/j.neuron.2011.12.039
5. ↑ Stölting G, Teodorescu G, Begemann B, Schubert J, Nabbout R, Toliat MR, Sander T, Nürnberg P, Lerche H, Fahlke C. Regulation of ClC-2 gating by intracellular ATP. Pflugers Arch. 2013 Oct;465(10):1423-37. PMID:23632988 doi:10.1007/s00424-013-1286-0
6. ↑ Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, van Berkel C, Polder E, Tollard E, Darios F, Brice A, de Die-Smulders CE, Vles JS, Vanderver A, Uziel G, Yalcinkaya C, Frints SG, Kalscheuer VM, Klooster J, Kamermans M, Abbink TE, Wolf NI, Sedel F, van der Knaap MS. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013 Jul;12(7):659-68. PMID:23707145 doi:10.1016/S1474-4422(13)70053-X
7. ↑ Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018 Mar;50(3):349-354. PMID:29403011 doi:10.1038/s41588-018-0048-5
8. ↑ Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, Schwarzmayr T, Strom TM, Jentsch TJ, Zennaro MC. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet. 2018 Mar;50(3):355-361. PMID:29403012 doi:10.1038/s41588-018-0053-8
9. ↑ Xu P, Chen Z, Ma J, Shan Y, Wang Y, Xie B, Zheng D, Guo F, Song X, Gao G, Ye K, Liu Y, Pan G, Jiang B, Peng F, Zhong X. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Hum Genet. 2023 Apr;142(4):577-593. PMID:36964785 doi:10.1007/s00439-023-02531-7
10. ↑ Xu M, Neelands T, Powers AS, Liu Y, Miller SD, Pintilie GD, Bois JD, Dror RO, Chiu W, Maduke M. CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism. Elife. 2024 Feb 12;12:RP90648. PMID:38345841 doi:10.7554/eLife.90648