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Gene Review

CLCA1  -  chloride channel accessory 1

Homo sapiens

Synonyms: CACC, CACC1, CLCRG1, CaCC, CaCC-1, ...
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Disease relevance of CLCA1


High impact information on CLCA1

  • CLCA proteins affect chloride conductance, epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, mucus production in asthma, and blood pressure [6].
  • The isoform with disrupted beta4-integrin binding (hCLCA1, pCLCA1, mCLCA3) alters epithelial mucus secretion and ion transport processes [6].
  • CLCA proteins were discovered in bovine trachea and named for a calcium-dependent chloride conductance found in trachea and in other secretory epithelial tissues [6].
  • New molecular candidates responsible for I(Cl.vol), I(Cl.Ca), and I( (ClC-3, CLCA1, and ClC-2, respectively) have recently been identified and are presently being evaluated [7].
  • Introduction of either gob-5 or hCLCA1, the human counterpart of gob-5, into the human mucoepidermoid cell line NCI-H292 induced mucus production as well as MUC5AC expression [8].

Chemical compound and disease context of CLCA1


Biological context of CLCA1

  • As non-pore-forming regulatory beta-subunits alter the kinetics and increase the Ca(2+) sensitivity of Ca(2+)-dependent K(+) channels (BK channels) we investigated whether co-expression of beta-subunits with CLCA1 would alter the kinetics/Ca(2+) sensitivity of mCLCA1 [11].
  • Both genes were mapped to adjacent loci on the short arm of chromosome 1 (1p22-31), a region to which the human CLCA1 had been assigned earlier [12].
  • Statistically significant association of the electrophysiological phenotype with the allele distribution of markers 5' of and within the CLCA locus was observed [13].
  • Interleukin-9 and Interleukin-13 augment UTP-induced Cl ion transport via hCLCA1 expression in a human bronchial epithelial cell line [4].
  • The results show clustering of all human CLCA family members known so far despite their moderately low levels of sequence homology and their heterogeneous expression patterns [12].

Anatomical context of CLCA1


Associations of CLCA1 with chemical compounds

  • HEK 293 cells transfected with CLCA1 exhibited an increase in whole-cell Ca2+-sensitive Cl- currents that were outwardly rectified and inhibited by 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid, dithiothreitol, and niflumic acid [1].
  • The CLCA gene family is a novel family of calcium-activated chloride channels [12].
  • 3. With the exception of the truncated secreted hCLCA3, all CLCA proteins are synthesized as an approximately 125 kDa precursor transmembrane glycoprotein that is rapidly cleaved into 90 and 35 kDa subunits [15].
  • 4. The CLCA proteins expressed on the luminal surface of lung vascular endothelia (bCLCA2; mCLCA1; hCLCA2) serve as adhesion molecules for lung metastatic cancer cells, mediating vascular arrest and lung colonization [15].
  • Moreover, niflumic acid (NFA), a blocker of hCLCA1-dependent Cl- efflux, inhibits MUC5A/C production in these cells [16].

Physical interactions of CLCA1

  • The corresponding CLCA-binding domain of the beta4 integrin is localized to the specific determining loop (SDL) [17].

Regulatory relationships of CLCA1

  • The expression of hCLCA1 protein was induced by IL-13 in a concentration-dependent manner [4].
  • We show here that hCLCA1 expression in NCI-H292 cells specifically induces soluble gel-forming mucin production [16].
  • MUC5AC mRNA and mucus protein expression was blocked by inhibiting hCLCA1 by using channel blockers (niflumic acid [NFA] and MSI-2216) without and with TNF-alpha stimulation [18].
  • METHODS: Expression of hCLCA1 and mucus was stimulated with TNF-alpha in human upper airway mucosal explant tissue [18].

Other interactions of CLCA1

  • Internal dialysis of human embryonic kidney cells stably expressing CLCA1 with 500 nM Ca(2+) evoked a significantly larger current when the beta-subunit KCNMB1 was co-expressed [11].
  • There was no association between CLCA2 and either CLCA1 or c-myc mRNA levels [3].
  • We have used suppression subtractive hybridization of mRNA from paired normal colon epithelium and tumor, followed by quantitative kinetic RT-PCR, to demonstrate that the transcription of two members of a novel Ca(2+)-dependent chloride channel family, CLCA1 and CLCA2, was significantly downregulated in approximately 80% of colorectal carcinomas [3].
  • Expression of hCLCA1 mRNA was colocalised with IL-9R expression and PAS-positive staining in epithelial cells [19].
  • That this signaling cascade is relevant to asthmatic hypersecretion was indicated by results showing that mucin induction by asthmatic tracheal aspirates was reduced by A1, CLCA1, and EGFR inhibitors [20].

Analytical, diagnostic and therapeutic context of CLCA1


  1. Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl- channel proteins. Gruber, A.D., Elble, R.C., Ji, H.L., Schreur, K.D., Fuller, C.M., Pauli, B.U. Genomics (1998) [Pubmed]
  2. CLCA1 gene polymorphisms in chronic obstructive pulmonary disease. Hegab, A.E., Sakamoto, T., Uchida, Y., Nomura, A., Ishii, Y., Morishima, Y., Mochizuki, M., Kimura, T., Saitoh, W., Massoud, H.H., Massoud, H.M., Hassanein, K.M., Sekizawa, K. J. Med. Genet. (2004) [Pubmed]
  3. Expression of the Ca2+-activated chloride channel genes CLCA1 and CLCA2 is downregulated in human colorectal cancer. Bustin, S.A., Li, S.R., Dorudi, S. DNA Cell Biol. (2001) [Pubmed]
  4. Interleukin-9 and Interleukin-13 augment UTP-induced Cl ion transport via hCLCA1 expression in a human bronchial epithelial cell line. Endo, Y., Isono, K., Kondo, M., Tamaoki, J., Nagai, A. Clin. Exp. Allergy (2007) [Pubmed]
  5. Novel conserved hydrolase domain in the CLCA family of alleged calcium-activated chloride channels. Pawłowski, K., Lepistö, M., Meinander, N., Sivars, U., Varga, M., Wieslander, E. Proteins (2006) [Pubmed]
  6. Structure and function of CLCA proteins. Loewen, M.E., Forsyth, G.W. Physiol. Rev. (2005) [Pubmed]
  7. Anion transport in heart. Hume, J.R., Duan, D., Collier, M.L., Yamazaki, J., Horowitz, B. Physiol. Rev. (2000) [Pubmed]
  8. Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma. Nakanishi, A., Morita, S., Iwashita, H., Sagiya, Y., Ashida, Y., Shirafuji, H., Fujisawa, Y., Nishimura, O., Fujino, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. The airway goblet cell. Rogers, D.F. Int. J. Biochem. Cell Biol. (2003) [Pubmed]
  10. Effect of phototherapy on the physiologic cholestasis of the neonate. Levi, N., Trevisan, M., Perini, R., Tamaro, G., Torre, G., Tiribelli, C. J. Pediatr. Gastroenterol. Nutr. (1984) [Pubmed]
  11. The large conductance potassium channel beta-subunit can interact with and modulate the functional properties of a calcium-activated chloride channel, CLCA1. Greenwood, I.A., Miller, L.J., Ohya, S., Horowitz, B. J. Biol. Chem. (2002) [Pubmed]
  12. Clustering of the human CLCA gene family on the short arm of chromosome 1 (1p22-31). Gruber, A.D., Pauli, B.U. Genome (1999) [Pubmed]
  13. The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis. Ritzka, M., Stanke, F., Jansen, S., Gruber, A.D., Pusch, L., Woelfl, S., Veeze, H.J., Halley, D.J., Tümmler, B. Hum. Genet. (2004) [Pubmed]
  14. Comparison of the properties of CLCA1 generated currents and I(Cl(Ca)) in murine portal vein smooth muscle cells. Britton, F.C., Ohya, S., Horowitz, B., Greenwood, I.A. J. Physiol. (Lond.) (2002) [Pubmed]
  15. Molecular characteristics and functional diversity of CLCA family members. Pauli, B.U., Abdel-Ghany, M., Cheng, H.C., Gruber, A.D., Archibald, H.A., Elble, R.C. Clin. Exp. Pharmacol. Physiol. (2000) [Pubmed]
  16. A calcium-activated chloride channel blocker inhibits goblet cell metaplasia and mucus overproduction. Zhou, Y., Shapiro, M., Dong, Q., Louahed, J., Weiss, C., Wan, S., Chen, Q., Dragwa, C., Savio, D., Huang, M., Fuller, C., Tomer, Y., Nicolaides, N.C., McLane, M., Levitt, R.C. Novartis Found. Symp. (2002) [Pubmed]
  17. The interacting binding domains of the beta(4) integrin and calcium-activated chloride channels (CLCAs) in metastasis. Abdel-Ghany, M., Cheng, H.C., Elble, R.C., Lin, H., DiBiasio, J., Pauli, B.U. J. Biol. Chem. (2003) [Pubmed]
  18. Niflumic acid and MSI-2216 reduce TNF-alpha-induced mucin expression in human airway mucosa. Hauber, H.P., Daigneault, P., Frenkiel, S., Lavigne, F., Hung, H.L., Levitt, R.C., Hamid, Q. J. Allergy Clin. Immunol. (2005) [Pubmed]
  19. Expression of HCLCA1 in cystic fibrosis lungs is associated with mucus overproduction. Hauber, H.P., Tsicopoulos, A., Wallaert, B., Griffin, S., McElvaney, N.G., Daigneault, P., Mueller, Z., Olivenstein, R., Holroyd, K.J., Levitt, R.C., Hamid, Q. Eur. Respir. J. (2004) [Pubmed]
  20. Adenosine up-regulation of the mucin gene, MUC2, in asthma. McNamara, N., Gallup, M., Khong, A., Sucher, A., Maltseva, I., Fahy, J., Basbaum, C. FASEB J. (2004) [Pubmed]
  21. hCLCA1 and mCLCA3 are secreted non-integral membrane proteins and therefore are not ion channels. Gibson, A., Lewis, A.P., Affleck, K., Aitken, A.J., Meldrum, E., Thompson, N. J. Biol. Chem. (2005) [Pubmed]
  22. Increased expression of the calcium-activated chloride channel hCLCA1 in airways of patients with obstructive chronic bronchitis. Hauber, H.P., Bergeron, C., Tsicopoulos, A., Wallaert, B., Olivenstein, R., Holroyd, K.J., Levitt, R.C., Hamid, Q. Can. Respir. J. (2005) [Pubmed]
  23. The calcium-dependent chloride conductance mediator pCLCA1. Loewen, M.E., Gabriel, S.E., Forsyth, G.W. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  24. A radioimmunoassay for lithocholic acid conjugates in human serum and liver tissue. Roda, A., Roda, E., Festi, D., Aldini, R., Mazzella, G., Sama, C., Barbara, L. Steroids (1978) [Pubmed]
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