Disease relevance of Clcn2

• Analysis of these results revealed that the membrane-delimited boundaries of the N- and C-termini of ClC-2 and the position of several extramembrane loops determined by these methods are largely similar to those predicted on the basis of the prokaryotic protein [ecClC (Escherichia coli ClC)] structures [1].
• In the present report, we examined the hypothesis that ClC-2 plays a role in regulatory volume decrease by expressing ClC-2 in Sf9 cells using the baculovirus system [2].
• Disruption of ClC-2-encoding gene in mouse leads to retinal and testicular degeneration and mutations in CLC2 (gene encoding the ClC-2 channel) are associated with idiopathic generalized epilepsies [3].

High impact information on Clcn2

• We now report on the precise intrarenal localization of the mRNAs coding for the chloride channels ClC-2, ClC-3 and ClC-5 [4].
• Expression of ClC-2 mRNA, encoding a swelling-activated chloride channel, could be demonstrated in the S3 segment of the proximal tubule [4].
• Molecular dissection of gating in the ClC-2 chloride channel [5].
• The ClC-2 chloride channel is probably involved in the regulation of cell volume and of neuronal excitability [5].
• Intracellular dialysis of anti-ClC-2 antibody inhibited expressed ClC-2 channels and endogenous Cl.ir currents in native rat and guinea pig cardiac myocytes [6].

Biological context of Clcn2

• These observations suggest that ClC-1 and ClC-2 may have evolved by gene duplication, mutation and DNA rearrangement [7].
• 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 [8].
• Exposure to tunicamycin to inhibit SP1 glycosylation reduces ClC-2 expression [8].
• ClC-2 is a CLC family member of chloride channels sensitive to changes in cell volume, pH and voltage [9].
• The ClC-2 promoter contains consensus binding sites within the first 237 bp, which bind transcription factors Sp1 and Sp3(1) [10].

Anatomical context of Clcn2

• The ClC-2 epithelial cell chloride channel is a voltage-, tonicity- and pH-regulated member of the ClC super family [7].
• Deletion of amino acids 16-61 in rat ClC-2 abolishes voltage and pH dependence in two-electrode voltage-clamp experiments in amphibian oocytes [11].
• Exposure of either cell line to high-dose glutamine is sufficient to induce glycosylation of SP1 and to induce and maintain ClC-2 [8].
• Antibodies against the COOH terminus of ClC-2 reacted with a protein between 90 and 100 kDa in liver plasma membranes [12].
• Taken together, these results indicate that dBcAMP-treated cultured rat cortical astrocytes express a Cl- inward rectifier, which exhibits similar but not identical features compared with those of the cloned and heterologously expressed hyperpolarization-activated Cl- channel ClC-2 [13].

Associations of Clcn2 with chemical compounds

• The maxi Cl- channel (p-VDAC) blocker Gd3+, the ClC-2 inhibitor Cd2+, and the MDR-1 blocker verapamil did not affect EAA release or VRAC currents [14].
• Functional characterization of novel alternatively spliced ClC-2 chloride channel variants in the heart [6].
• 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 [8].
• Aldosterone studies suggest that ClC-2 expression in the kidney may be hormonally regulated [9].
• These results suggest that ClC-2 may be involved in estrogen-induced Cl(-) transport in rat kidney [9].
• We conclude that the cholesterol environment regulates ClC-2 activity, and we provide evidence that the increase in ClC-2 activity in response to acute oxidative or metabolic stress involves relocalization of this channel to DSM [15].

Regulatory relationships of Clcn2

• Modulation of Sp1 and Sp3 in lung epithelial cells regulates ClC-2 chloride channel expression [10].
• ClC-2 is a pH- and voltage-activated chloride channel, which is highly expressed in fetal airways and downregulated at birth [10].

Other interactions of Clcn2

• Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1 [8].
• The levels of ClC-2 in both atria and ventricles were significantly less than those measured for ClC-3 (n = 3; P < 0.05) [16].
• Electron microscopy and double immunostaining using antibodies against chloride channel-2 and glial fibrillary acidic protein confirmed that the dense network of chloride channel-2-positive processes corresponds to the end feet of astrocytes [17].
• Arginine vasopressin regulates CFTR and ClC-2 mRNA expression in rat kidney cortex and medulla [18].
• Using Western Blotting, we found protein expression of ClC-2 and ClC-7, but not ClC-3, in RCMC, whereas in PMC neither of these proteins could be detected [19].

Analytical, diagnostic and therapeutic context of Clcn2

• Time-dependent inward Cl- currents and a ClC-2-specific RT-PCR product were also observed in WIF-B cells but not HEK293T cells [12].
• The renal ClC-2 protein expression was analyzed by Western blot [9].
• The decreased renal expression of ClC-2 mRNA and protein observed in ovariectomized rats was restored to control levels after treatment with low doses of estradiol [9].
• To explore the possibility that estrogen control ClC-2 expression, we investigated whether its expression changed in the kidney of female Wistar rats subjected to ovariectomy with or without near-physiological or high doses of 17beta-estradiol benzoate treatment for 10 days [9].
• Site-directed mutagenesis was used to understand ClC-2 activation in response to cell swelling, hyperpolarization and acidic extracellular pH [5].

References