The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis

Ritzka, Margit; Stanke, Frauke; Jansen, Silke; Gruber, Achim D.; Pusch, Larissa; Woelfl, Stefan; Veeze, Henk J.; Halley, Dicky; Tümmler, Burkhard

doi:10.1007/s00439-004-1190-y

Cited by 51 publications

(63 citation statements)

References 58 publications

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“…Enhanced expression of Lpl has been observed in dextran sulfate sodium-induced colitis in hamsters (18). ClCa4 is considered to be an important molecule for the induction of diarrhea in cystic fibrosis (19). Gpx2 is a marker for the colonic inflammation that occurs in experimental colitis and inflammatory bowel diseases (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine

et al. 2011

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“…In particular, the gene locus of the human hCLCA1 and hCLCA4, the ortholog of mCLCA6, has been identified as a modulator of the basic chloride secretory defect in CFTRdeficient CF patients (Ritzka et al 2004). Questions remain whether CLCA proteins are involved in the alternative calcium-activated chloride conductance that has been proposed to partially compensate for the chloride secretory defect in CF (Rozmahel et al (Gruber et al 1998b;Leverkoehne et al 2006), mCLCA3 (yellow) in secretory vesicles of goblet cells (Romio et al 1999;Leverkoehne and Gruber 2002), mCLCA4 (orange) in smooth muscle cells , and mCLCA6 (red) on the apical surface of non-goblet cell enterocytes in the small intestinal villi (left panel) and throughout the large intestinal crypts (right panel).…”

Section: Discussionmentioning

confidence: 99%

Murine mCLCA6 Is an Integral Apical Membrane Protein of Non-goblet Cell Enterocytes and Co-localizes With the Cystic Fibrosis Transmembrane Conductance Regulator

Bothe

Braun

Mundhenk

et al. 2008

J Histochem Cytochem.

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The CLCA family of proteins consists of a growing number of structurally and functionally diverse members with distinct expression patterns in different tissues. Several CLCA homologs have been implicated in diseases with secretory dysfunctions in the respiratory and intestinal tracts. Here we present biochemical protein characterization and details on the cellular and subcellular expression pattern of the murine mCLCA6 using specific antibodies directed against the amino- and carboxy-terminal cleavage products of mCLCA6. Computational and biochemical characterizations revealed protein processing and structural elements shared with hCLCA2 including anchorage in the apical cell membrane by a transmembrane domain in the carboxy-terminal subunit. A systematic light- and electron-microscopic immunolocalization found mCLCA6 to be associated with the microvilli of non-goblet cell enterocytes in the murine small and large intestine but in no other tissues. The expression pattern was confirmed by quantitative RT-PCR following laser-capture microdissection of relevant tissues. Confocal laser scanning microscopy colocalized the mCLCA6 protein with the cystic fibrosis transmembrane conductance regulator CFTR at the apical surface of colonic crypt cells. Together with previously published functional data, the results support a direct or indirect role of mCLCA6 in transepithelial anion conductance in the mouse intestine.

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“…First, transfection of any CLCA cDNA into 293T or other heterologous cell types results in a calcium-stimulated chloride current across the plasma membrane (14,15). Second, genetic modifiers of the severity of cystic fibrosis and asthma, both secretory diseases in which chloride flux plays a prominent role, map to the CLCA gene cluster (16,17). The identification of interacting proteins should allow a better definition of the functions of this protein family and permit an accurate renaming.…”

Section: Discussionmentioning

confidence: 99%

“…When transfected into 293T cells, CLCA isoforms from mouse, human, bovine, pig, and rat produce a chloride current in response to calcium ionophores or calcium release from the endoplasmic reticulum (ER) (14,15). Genetic studies link the CLCA family to the secretory disorders cystic fibrosis and asthma (16,17). On the other hand, disruption of CLCA expression in cancer has been reported for several CLCA genes, especially hCLCA2 and its mouse ortholog mCLCA5 (5,7,18).…”

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confidence: 99%

The Putative Chloride Channel hCLCA2 Has a Single C-terminal Transmembrane Segment

Elble

Walia

Cheng

et al. 2006

Journal of Biological Chemistry

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Calcium-activated chloride channel (CLCA) proteins were first described as a family of plasma membrane Cl ؊ channels that could be activated by calcium. Genetic and electrophysiological studies have supported this view. The human CLCA2 protein is expressed as a 943-amino-acid precursor whose N-terminal signal sequence is removed followed by internal cleavage near amino acid position 680. Earlier investigations of transmembrane geometry suggested five membrane passes. However, analysis by the more recently derived simple modular architecture research tool algorithm predicts that a C-terminal 22-amino-acid hydrophobic segment comprises the only transmembrane pass. To resolve this question, we raised an antibody against hCLCA2 and investigated the synthesis, localization, maturation, and topology of the protein. Cell surface biotinylation and endoglycosidase H analysis revealed a 128-kDa precursor confined to the endoplasmic reticulum and a maturely glycosylated 141-kDa precursor at the cell surface by 48 h post-transfection. By 72 h, 109-kDa N-terminal and 35-kDa C-terminal cleavage products were detected at the cell surface but not in the endoplasmic reticulum. Surprisingly, however, the 109-kDa product was spontaneously shed into the medium or removed by acid washes, whereas the precursor and 35-kDa product were retained by the membrane. Two other CLCA family members, bCLCA2 and hCLCA1, also demonstrated preferential release of the N-terminal product. Transfer of the hCLCA2 C-terminal hydrophobic segment to a secreted form of green fluorescent protein was sufficient to target that protein to the plasma membrane. Together, these data indicate that hCLCA2 is mostly extracellular with only a single transmembrane segment followed by a short cytoplasmic tail and is itself unlikely to form a channel.The calcium-activated chloride channel (CLCA) 2 family was first identified nearly simultaneously by independent laboratories as either a calcium-activated chloride channel expressed in bovine respiratory epithelium (1) or as a cell adhesion molecule expressed in bovine vascular endothelium (2). Homologs were subsequently identified in other species, with at least six in mouse and four in human (3-12). With the sequencing of numerous genomes, it has become apparent that CLCA proteins are found throughout the chordates and possibly in some invertebrates (13). 3The exact function of these proteins remains unclear. When transfected into 293T cells, CLCA isoforms from mouse, human, bovine, pig, and rat produce a chloride current in response to calcium ionophores or calcium release from the endoplasmic reticulum (ER) (14, 15). Genetic studies link the CLCA family to the secretory disorders cystic fibrosis and asthma (16,17). On the other hand, disruption of CLCA expression in cancer has been reported for several CLCA genes, especially hCLCA2 and its mouse ortholog mCLCA5 (5,7,18). In addition, several CLCA proteins have been found to interact with ␤4 integrin (19 -21).A common feature of the CLCA family is proteolytic cleavage....

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The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis

Cited by 51 publications

References 58 publications

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine

Effects of Bifidobacterium breve on inflammatory gene expression in neonatal and weaning rat intestine

Murine mCLCA6 Is an Integral Apical Membrane Protein of Non-goblet Cell Enterocytes and Co-localizes With the Cystic Fibrosis Transmembrane Conductance Regulator

The Putative Chloride Channel hCLCA2 Has a Single C-terminal Transmembrane Segment

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