Disease relevance of CLCA1

• These findings suggest that human CLCA1 mediates a Ca2+-activated Cl- conductance in the human intestine and make it an interesting candidate as a modulating factor in the pathogenesis of cystic fibrosis [1].
• CLCA1 gene polymorphisms in chronic obstructive pulmonary disease [2].
• Our results suggest that CLCA1 could specify a new tumor suppressor and that, as in breast cancer, CLCA2 may function as a tumor suppressor in colorectal cancer [3].
• Background IL-9 and IL-13 induce airway goblet cell metaplasia, which is associated with expression of a Ca(2+)-activated Cl channel, hCLCA1 [4].
• Fragments of CLCA1 corresponding to the modeled hydrolase domain were expressed in Escherichia coli, and the resulting proteins were readily refolded into monomeric soluble protein, indicating formation of stable independent domains [5].

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(Cl.ir) (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

• Novel therapeutic strategies to prevent or reverse goblet cell hyperplasia include inhibitors of EGF receptor tyrosine kinase and CLCA, of which viable pharmaceutical molecules are now available for clinical trial in hypersecretory conditions of the airways [9].
• We investigated the effect of PT on the levels of serum total bile acids (STBA), conjugated cholic acid (CCA), conjugated chenodeoxycholic acid (CCDCA), conjugated lithocholic acid (CLCA), and sulfolithocholylglycine (SLCG) in 13 neonates with unconjugated nonhemolytic hyperbilirubinemia before and after 12 h of PT [10].

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

• In normal colon epithelium, CLCA1 mRNA levels were significantly associated with c-myc transcription but became decoupled in the tumor samples [3].
• The morphology of epithelial cells was assessed by light microscopic findings, and hCLCA1 expression was investigated by immunocytochemistry and immunoblotting [4].
• Expression of hCLCA1 and hCLCA4 in human rectal mucosa was proven by microarray analysis [13].
• The CLCA gene region was identified to encode mediators of DIDS-sensitive anion conductance in the human gastrointestinal tract that modulate the CF basic defect [13].
• Comparison of the properties of CLCA1 generated currents and I(Cl(Ca)) in murine portal vein smooth muscle cells [14].

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

• The N-terminal cleavage products of hCLCA1 and mCLCA3 could be detected in bronchoalveolar lavage fluid taken from asthmatic subjects and ovalbumin-challenged mice, demonstrating release from cells in a physiological setting [21].
• Additionally, in situ hybridization was performed to determine the expression of hCLCA1 messenger RNA [22].
• Laser capture microdissection was performed to quantify hCLCA1 and MUC5AC mRNA expression in epithelial cells derived from mucosal explant tissue [18].
• Notable differences of pCLCA1 from the reported properties of CLCA family members include the failure of phorbol 12-myristate 13-acetate to activate chloride efflux in cells expressing pCLCA1 and a lack of inhibition of chloride efflux from these cells after treatment with DIDS or dithiothreitol [23].
• A sensitive and specific radioimmunoassay for glycine and taurine conjugates of lithocholic acid (CLCA) has been developed [24].

References