Disease relevance of CLCN2

• Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies [1].
• Prominent ClC-2, -3, and -5 channel expression was also detected in acute patient biopsies from low- and high-grade malignant gliomas [2].
• CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity [3].
• Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene [3].
• To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background [4].

Psychiatry related information on CLCN2

• Thus, cell surface expression of ClC-2 may be regulated by dynein motor activity [5].

High impact information on CLCN2

• 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 [6].
• M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition [1].
• In this issue of Neuron, Jentsch, Pusch, and colleagues use the structure of a bacterial ClC homolog to guide a mutagenic analysis of inhibitor binding to ClC-0, ClC-1, and ClC-2 [7].
• Consistent with this hypothesis, we show that heterologously expressed rat ClC-2 is also activated by serine/threonine dephosphorylation, suggesting that the two channels have common regulatory mechanisms [8].
• Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells [9].

Chemical compound and disease context of CLCN2

• Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation [10].
• Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies [11].

Biological context of CLCN2

• CLCN2 gene expression was predominantly influenced by cell volume regulation while that of CLCN3 was preferentially affected by conditions associated with TM pathology [12].
• We suggest that ClC-2 and ClC-3 channels are specifically upregulated in glioma membranes and endow glioma cells with an enhanced ability to transport Cl-. This may in turn facilitate rapid changes in cell size and shape as cells divide or invade through tortuous extracellular brain spaces [2].
• CONCLUSIONS: CLC-2 is not a key modifier gene of CF lung phenotype [3].
• METHODS: The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%) [3].
• We have cloned a cDNA from the human epithelial cell line T84 whose predicted amino acid sequence shows 93.9% identity with rat CIC-2 [13].

Anatomical context of CLCN2

• In situ hybridization localized the CLCN2 and CLCN3 messages to airway and distal pulmonary epithelia and to pulmonary blood vessels [14].
• However, for CLC-2, no band was apparent around the predicted size from fresh and cultured corneal endothelium [15].
• The human Ca2+-activated chloride channel-2 (CLCA2) is expressed in normal breast epithelium but not in breast tumors of different stages of progression [16].
• In conclusion, activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival [17].
• Disruption of dynein motor function perturbs ClC-2 localization and increases the functional expression of ClC-2 in the plasma membranes of COS7 cells [5].

Associations of CLCN2 with chemical compounds

• Further, other studies suggest that ClC-2 expression in neurons may modify inhibitory synaptic transmission via the gamma-aminobutyric acid, type A receptor [5].
• Either RRAT or RGET was sufficient for PKA activation of hClC-2 at pH(o) 7.4, as long as phosphatase inhibitors (cyclosporin A or endothal) were present [18].
• Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans [10].
• It has been controversial whether the ClC-2 chloride channel is involved in hydrochloric acid secretion of gastric parietal cells [19].
• In the rat, ClC-2 was present in the lateral membranes of villus enterocytes and was predominant at the basolateral membranes of luminal colon enterocytes [20].

Regulatory relationships of CLCN2

• Hypotonic conditions consistently up regulated CLCN2 and slightly up regulated CLCN3 [12].
• CIC-2 is a voltage- and volume-regulated chloride channel expressed in many tissues [21].
• These data suggest that IFN-gamma activates ClC-2 channel activity in lung epithelial cells via mRNA stabilization [22].
• TGF-alpha (0.17 nM) irreversibly inhibited ClC-2 current in nystatin-perforated whole cell patch-clamp experiments, whereas a superimposed reversible activation of the current was observed at 8.3 nM TGF-alpha [23].

Other interactions of CLCN2

• We determined the ontogeny of expression of the CLCN family of voltage-dependent Cl channel genes (CLCN2 through 6, K(a) and K(b)) in the human lung to identify potential pathways for pulmonary liquid secretion [14].
• DEX treatment markedly down regulated CLCN3 and little, if any, reduced ClC-2 [12].
• The properties of the vesicles' Cl- conductance resemble those of the intermediate conductance outwardly rectifying Cl- channel and tentatively exclude contributions of CFTR, pICln and ClC-2 [24].
• CLCN2 and idiopathic generalized epilepsy [25].
• Activation of chloride currents was also observed after introducing homologous mutations in ClC-Ka and ClC-K1, but not in ClC-2 and ClC-5 chloride channels [26].

Analytical, diagnostic and therapeutic context of CLCN2

• Semi-quantitative RT-PCR and Northern blot analysis showed that ClC-3 was most abundantly expressed in all cells regardless of the cell types and maturity, while expression of ClC-2 was weak in these cells [27].
• RESULTS: PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20 [3].
• Mass spectrometry and Western blot analysis of eluate from a ClC-2 affinity matrix showed that heavy and intermediate chains of dynein bind ClC-2 in vitro [5].
• We have studied the distribution of ClC-2 in adult human and rat intestine and airways by immunoblotting and confocal microscopy [20].
• Immunohistochemistry on the rat gastric mucosa showed no significant expression of ClC-2 protein in the parietal cells which showed abundant expression of H+,K+-ATPase [19].

References