Disease relevance of Clcn2

• It is concluded that ClC-2 is unlikely to be a candidate rescue channel in cystic fibrosis [1].
• The Clc2 gene of the mouse codes for the ubiquitously expressed chloride channel ClC-2, a member of a family of at least seven voltage gated chloride channels, some of which are implicated in hereditary diseases [2].
• Several important functions have been attributed to ClC-2, but contrary to these expectations ClC-2-deficient mice lacked overt abnormalities except for a severe degeneration of the retina and the testes, which led to selective male infertility [3].

High impact information on Clcn2

• Tubules were filled with abnormal Sertoli cells, which normally express ClC-2 in patches adjacent to germ cells [3].
• Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption [3].
• Colon expressing wild-type CFTR even secreted more Cl(-) when ClC-2 was disrupted, although CFTR transcript levels were unchanged [1].
• Because the broadly expressed plasma membrane Cl(-) channel, ClC-2, is present in the tissues whose function is compromised in cystic fibrosis, we generated mice with a disruption of both Cl(-) channel genes [1].
• Surprisingly, mice expressing mutant CFTR (deletion of phenylalanine 508), survived longer when ClC-2 was disrupted additionally [1].

Biological context of Clcn2

• Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models [1].
• Chloride channel 2 gene (Clc2) maps to chromosome 16 of the mouse, extending a region of conserved synteny with human chromosome 3q [2].
• Exposure to tunicamycin to inhibit SP1 glycosylation reduces ClC-2 expression [4].
• A 2005 bp clone was isolated from a rat choroid plexus cDNA library using a probe for ClC-2 [5].
• Our results support the hypothesis that glycosylation of SP1 produces the 105-kD isoform of SP1 and is involved in regulating ClC-2 gene expression [4].

Anatomical context of Clcn2

• 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 [6].
• The basolateral membrane localization of ClC-2 in absorptive cells of the duodenum and the colon is compatible with an absorptive function for this Cl- channel [6].
• ClC-2 was sorted to the basolateral membranes in MDCK, Caco-2 and LLC-PK1-mu1B, but not in LLC-PK1-mu1A cells [6].
• ClC-2 was exclusively localized at the basolateral membranes of surface colonic cells or villus duodenal enterocytes [6].
• Astrocytes from mouse brain slices express ClC-2-mediated Cl- currents regulated during development and after injury [7].

Associations of Clcn2 with chemical compounds

• Exposure of either cell line to high-dose glutamine is sufficient to induce glycosylation of SP1 and to induce and maintain ClC-2 [4].
• A high level of luminal ClC-2 protein expression is maintained by the SP1 transcription factor until SP1 and ClC-2 decline rapidly at birth [4].

Regulatory relationships of Clcn2

• Of interest is the finding that the ClC-2 mRNA is expressed about the same level in duodena from both CFTR knockout and wild-type mice [8].

Other interactions of Clcn2

• The disruption of ClC-2, in addition to CFTR, did not decrease Cl(-) secretion [1].
• Using a mouse interspecies back-cross panel, we have mapped Clc2 to Chr 16, proximal to the somatostatin gene Smst, extending a region of documented conserved synteny to human Chr 3q [2].
• Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1 [4].

Analytical, diagnostic and therapeutic context of Clcn2

• RT-PCR, using specific ClC-2 primers, amplified a 238 bp fragment of mRNA from rat choroid plexus, which was 99 % identical to the 5' sequence of rat ClC-2 [5].
• Inward-rectifying anion channels were observed in whole-cell recordings of choroid plexus epithelial cells isolated from ClC-2 knock-out mice [5].
• Assessment of the native expression pattern of ClC-2 protein in the murine intestinal epithelium by confocal and electron microscopy showed that ClC-2 exhibits a novel distribution, a distribution pattern somewhat unexpected for a channel involved in chloride secretion [9].
• Reverse transcription polymerase chain reaction and Northern blot analysis confirmed transcriptional expression of ClC-2 in both atrial and ventricular tissues and isolated myocytes of mouse and guinea pig hearts [10].

References