Chloride channel protein 2

Details

Name

Chloride channel protein 2

Kind

protein

Synonyms

• ClC-2

Gene Name

CLCN2

UniProtKB Entry

P51788Swiss-Prot

Organism

Humans

NCBI Taxonomy ID

9606

Amino acid sequence

>lcl|BSEQ0037070|Chloride channel protein 2
MAAAAAEEGMEPRALQYEQTLMYGRYTQDLGAFAKEEAARIRLGGPEPWKGPPSSRAAPE
LLEYGRSRCARCRVCSVRCHKFLVSRVGEDWIFLVLLGLLMALVSWVMDYAIAACLQAQQ
WMSRGLNTSILLQYLAWVTYPVVLITFSAGFTQILAPQAVGSGIPEMKTILRGVVLKEYL
TLKTFIAKVIGLTCALGSGMPLGKEGPFVHIASMCAALLSKFLSLFGGIYENESRNTEML
AAACAVGVGCCFAAPIGGVLFSIEVTSTFFAVRNYWRGFFAATFSAFIFRVLAVWNRDEE
TITALFKTRFRLDFPFDLQELPAFAVIGIASGFGGALFVYLNRKIVQVMRKQKTINRFLM
RKRLLFPALVTLLISTLTFPPGFGQFMAGQLSQKETLVTLFDNRTWVRQGLVEELEPPST
SQAWNPPRANVFLTLVIFILMKFWMSALATTIPVPCGAFMPVFVIGAAFGRLVGESMAAW
FPDGIHTDSSTYRIVPGGYAVVGAAALAGAVTHTVSTAVIVFELTGQIAHILPVMIAVIL
ANAVAQSLQPSLYDSIIRIKKLPYLPELGWGRHQQYRVRVEDIMVRDVPHVALSCTFRDL
RLALHRTKGRMLALVESPESMILLGSIERSQVVALLGAQLSPARRRQHMQERRATQTSPL
SDQEGPPTPEASVCFQVNTEDSAFPAARGETHKPLKPALKRGPSVTRNLGESPTGSAESA
GIALRSLFCGSPPPEAASEKLESCEKRKLKRVRISLASDADLEGEMSPEEILEWEEQQLD
EPVNFSDCKIDPAPFQLVERTSLHKTHTIFSLLGVDHAYVTSIGRLIGIVTLKELRKAIE
GSVTAQGVKVRPPLASFRDSATSSSDTETTEVHALWGPHSRHGLPREGSPSDSDDKCQ

Number of residues

898

Molecular Weight

98534.425

Theoretical pI

8.47

GO Classification

Processes

acinar cell differentiation / chloride transport / lung development / phagocytosis, engulfment / positive regulation of oligodendrocyte differentiation / regulation of aldosterone biosynthetic process

Components

astrocyte end-foot / axon / basolateral plasma membrane / dendritic spine membrane / myelin sheath / perikaryon / postsynaptic membrane

General Function

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)

Specific Function

voltage-gated chloride channel activity

Pfam Domain Function

• Voltage_CLC (PF00654)

Signal Regions

Not Available

Transmembrane Regions

88-121 130-155 180-198 205-223 275-295 321-349 358-377 429-449 457-480 531-548

Cellular Location

Cell membrane

Gene sequence

>lcl|BSEQ0010542|Chloride channel protein 2 (CLCN2)
ATGGCGGCCGCGGCGGCGGAGGAAGGGATGGAGCCACGGGCGCTGCAGTACGAGCAGACC
CTGATGTATGGCCGGTACACTCAGGACCTTGGGGCCTTTGCCAAAGAGGAAGCTGCTCGG
ATTCGCCTGGGAGGGCCTGAACCCTGGAAAGGTCCCCCTTCCTCTCGGGCTGCCCCAGAG
CTCTTGGAATATGGACGGAGCCGTTGCGCCCGATGCCGCGTCTGTTCTGTCCGCTGCCAC
AAGTTCCTAGTATCCAGGGTTGGTGAAGATTGGATCTTCCTGGTCCTGCTGGGGCTTCTC
ATGGCATTGGTCAGCTGGGTCATGGACTATGCCATTGCTGCCTGTCTGCAAGCCCAGCAG
TGGATGTCCCGGGGCTTGAACACCAGCATCTTGCTCCAGTACCTGGCCTGGGTCACCTAC
CCTGTTGTCCTCATCACTTTCTCAGCCGGATTCACACAGATCCTGGCCCCTCAGGCTGTC
GGCTCTGGCATCCCTGAGATGAAGACCATCTTGCGGGGAGTGGTGCTGAAAGAATACCTC
ACACTCAAGACCTTTATAGCTAAGGTCATTGGGCTGACCTGCGCCCTAGGCAGCGGGATG
CCGCTTGGCAAAGAGGGCCCTTTTGTGCATATCGCAAGCATGTGTGCTGCCCTTCTCAGC
AAGTTCCTCTCCCTCTTTGGGGGTATCTATGAGAATGAATCCCGGAACACAGAGATGCTG
GCTGCCGCCTGTGCCGTGGGGGTGGGCTGCTGCTTCGCGGCACCTATTGGAGGCGTCCTC
TTCAGCATCGAGGTCACCTCCACCTTCTTTGCAGTGCGGAACTACTGGCGGGGCTTCTTC
GCTGCCACCTTCAGTGCCTTCATCTTCCGGGTCTTGGCAGTCTGGAACCGGGATGAAGAG
ACTATTACAGCCCTCTTCAAAACCCGATTCCGGCTCGACTTCCCCTTTGACCTGCAGGAG
CTGCCAGCCTTTGCTGTCATTGGTATTGCTAGTGGCTTCGGTGGAGCCCTCTTTGTCTAC
CTGAACCGGAAGATTGTCCAGGTGATGCGGAAGCAGAAAACCATCAATCGCTTCCTCATG
AGGAAACGCCTGCTCTTCCCGGCTCTGGTGACCCTGCTCATCTCCACGCTGACCTTCCCC
CCTGGCTTTGGACAGTTCATGGCTGGACAGCTCTCACAGAAAGAGACGCTGGTCACCCTG
TTTGACAATCGGACGTGGGTCCGCCAGGGCCTGGTGGAGGAGCTAGAACCACCCAGCACC
TCACAGGCCTGGAACCCACCACGTGCCAACGTCTTCCTCACCCTGGTCATCTTCATTCTC
ATGAAGTTCTGGATGTCTGCACTGGCCACCACCATCCCAGTTCCCTGTGGGGCCTTCATG
CCTGTCTTTGTCATTGATGGAATTCATACGGACAGCAGCACCTACCGGATTGTGCCTGGG
GGCTACGCTGTGGTCGGGGCAGCTGCGCTGGCAGGAGCGGTGACACACACAGTGTCCACG
GCTGTGATCGTGTTCGAGCTCACAGGCCAGATTGCCCACATCCTGCCTGTCATGATCGCC
GTCATCCTGGCCAACGCTGTCGCCCAGAGTCTGCAGCCCTCCCTCTATGACAGCATCATC
CGAATCAAGAAACTGCCCTACCTGCCTGAGCTCGGCTGGGGCCGCCACCAGCAGTACCGG
GTGCGTGTGGAGGACATCATGGTGCGGGATGTTCCCCATGTGGCCCTCAGCTGCACCTTC
CGGGACCTGCGTTTGGCACTGCACAGGACCAAGGGCCGAATGCTGGCCCTAGTGGAGTCC
CCTGAGTCCATGATTCTGCTGGGCTCCATCGAGCGTTCACAGGTGGTGGCATTGTTGGGG
GCCCAGCTGAGCCCAGCCCGCCGGCGGCAGCACATGCAGGAGCGCAGAGCCACCCAGACC
TCTCCACTATCTGATCAGGAGGGTCCCCCTACCCCTGAGGCTTCTGTCTGCTTCCAGGTG
AACACAGAAGACTCAGCCTTCCCAGCAGCCCGGGGGGAGACCCACAAGCCCCTAAAGCCT
GCACTCAAGAGGGGGCCCAGTGTCACCAGGAACCTCGGAGAGAGTCCCACAGGGAGCGCA
GAGTCGGCAGGCATCGCCCTCCGGAGCCTCTTCTGTGGCAGTCCACCCCCTGAGGCTGCT
TCGGAGAAGTTGGAATCCTGTGAGAAGCGCAAGCTGAAGCGTGTCCGAATCTCCCTGGCA
AGTGACGCGGACCTGGAAGGCGAGATGAGCCCTGAAGAGATTCTGGAGTGGGAGGAGCAG
CAACTAGATGAACCTGTCAACTTCAGTGACTGCAAAATTGATCCTGCTCCCTTCCAGCTG
GTGGAGCGGACCTCTTTGCACAAGACTCACACTATCTTCTCACTGCTGGGAGTGGACCAT
GCTTATGTCACCAGTATTGGCAGACTCATTGGAATCGTTACTCTAAAGGAGCTCCGGAAG
GCCATCGAGGGCTCTGTCACAGCACAGGGTGTGAAAGTCCGGCCGCCCCTCGCCAGCTTC
CGAGACAGTGCCACCAGCAGCAGTGACACGGAGACCACTGAGGTGCATGCACTCTGGGGG
CCCCACTCCCGTCATGGCCTCCCCCGGGAGGGCAGCCCTTCCGACAGCGACGACAAATGC
CAATGA

Chromosome Location

3

Locus

3q27.1

External Identifiers

Resource	Link
UniProtKB ID	P51788
UniProtKB Entry Name	CLCN2_HUMAN
GenBank Protein ID	2570864
GenBank Gene ID	AF026004
GeneCard ID	CLCN2
GenAtlas ID	CLCN2
HGNC ID	HGNC:2020
PDB ID(s)	7XF5, 7XJA, 8GQU, 8TA2, 8TA3, 8TA4, 8TA5, 8TA6
KEGG ID	hsa:1181
IUPHAR/Guide To Pharmacology ID	699
NCBI Gene ID	1181

General References

1. Cid LP, Montrose-Rafizadeh C, Smith DI, Guggino WB, Cutting GR: Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues. Hum Mol Genet. 1995 Mar;4(3):407-13. [Article]
2. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
3. Muzny DM, Scherer SE, Kaul R, Wang J, Yu J, Sudbrak R, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Wei S, Wheeler DA, Wright MW, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clendenning J, Clerc-Blankenburg KP, Chen R, Chen Z, Davis C, Delgado O, Dinh HH, Dong W, Draper H, Ernst S, Fu G, Gonzalez-Garay ML, Garcia DK, Gillett W, Gu J, Hao B, Haugen E, Havlak P, He X, Hennig S, Hu S, Huang W, Jackson LR, Jacob LS, Kelly SH, Kube M, Levy R, Li Z, Liu B, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Palmeiri A, Pasternak S, Perez LM, Phelps KA, Plopper FJ, Qiang B, Raymond C, Rodriguez R, Saenphimmachak C, Santibanez J, Shen H, Shen Y, Subramanian S, Tabor PE, Verduzco D, Waldron L, Wang J, Wang J, Wang Q, Williams GA, Wong GK, Yao Z, Zhang J, Zhang X, Zhao G, Zhou J, Zhou Y, Nelson D, Lehrach H, Reinhardt R, Naylor SL, Yang H, Olson M, Weinstock G, Gibbs RA: The DNA sequence, annotation and analysis of human chromosome 3. Nature. 2006 Apr 27;440(7088):1194-8. [Article]
4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
5. Lamb FS, Clayton GH, Liu BX, Smith RL, Barna TJ, Schutte BC: Expression of CLCN voltage-gated chloride channel genes in human blood vessels. J Mol Cell Cardiol. 1999 Mar;31(3):657-66. [Article]
6. Niemeyer MI, Cid LP, Yusef YR, Briones R, Sepulveda FV: Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons. J Physiol. 2009 Apr 1;587(Pt 7):1387-400. doi: 10.1113/jphysiol.2008.167353. Epub 2009 Jan 19. [Article]
7. Haug K, Warnstedt M, Alekov AK, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller-Newen G, Propping P, Elger CE, Fahlke C, Lerche H, Heils A: Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003 Apr;33(4):527-32. Epub 2003 Mar 3. [Article]
8. Haug K, Warnstedt M, Alekov AK, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller-Newen G, Propping P, Elger CE, Fahlke C, Lerche H: Retraction: Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2009 Sep;41(9):1043. doi: 10.1038/ng0909-1043. [Article]
9. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]
10. Paul J, Jeyaraj S, Huber SM, Seebohm G, Bohmer C, Lang F, Kremsner PG, Kun JF: Alterations in the cytoplasmic domain of CLCN2 result in altered gating kinetics. Cell Physiol Biochem. 2007;20(5):441-54. [Article]
11. Combi R, Grioni D, Contri M, Redaelli S, Redaelli F, Bassi MT, Barisani D, Lavitrano ML, Tredici G, Tenchini ML, Bertolini M, Dalpra L: Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy. Brain Res Bull. 2009 Apr 29;79(2):89-96. doi: 10.1016/j.brainresbull.2009.01.008. Epub 2009 Feb 5. [Article]
12. Kleefuss-Lie A, Friedl W, Cichon S, Haug K, Warnstedt M, Alekov A, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller-Newen G, Propping P, Elger CE, Fahlke C, Lerche H: CLCN2 variants in idiopathic generalized epilepsy. Nat Genet. 2009 Sep;41(9):954-5. doi: 10.1038/ng0909-954. [Article]
13. 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. doi: 10.1002/humu.20876. [Article]
14. 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. doi: 10.1016/S1474-4422(13)70053-X. Epub 2013 May 22. [Article]

Associated Data

Drug Relations

Drug	Drug group	Pharmacological action?	Type	Actions	Details
Lubiprostone	approved, investigational	yes	target	inducer	Details
Cobiprostone	investigational	unknown	target		Details
Hydroxyfasudil	experimental	yes	target	activator	Details