CLCN2 Membrane Protein Introduction

Introduction of CLCN2

CLCN2 is one of the nine mammalian members of the ClC chloride channel family. It can be slowly activated by hyperpolarization and then be further activated by extracellular acidification or hypotonic cell swelling. CLCN2 is expressed in many tissues, such as the brain, intestine, kidney, stomach, salivary glands and heart. Although a clear understanding of its physiological function remains to be determined, a growing body of evidence suggests that CLCN2 can play different roles, depending on which tissue it is expressed in.

Function of CLCN2 Membrane Protein

ClCN2 takes part in many important biological processes. Recent researches have shown us that disordered function of the ClCN2-encoding gene in the mouse will directly lead to degeneration of male germ cells and photoreceptors, which may be a result of a defect in transepithelial transport across Sertoli cells and the retinal pigment epithelium. It also participates in fluid secretion in the murine small intestine or in fluid absorption in the colon. The results got from hippocampus cells or transfected dorsal root ganglion neurons suggest that ClCN2 has been implicated in the regulating of the effects of GABAA receptor action by controlling intracellular chloride concentration. In humans, mutations in the gene ClCN2, which can be predicted to cause hyperexcitability of GABAergic synapses, have recently been found to be associated with idiopathic generalized epilepsies.

Fig 1. ClC-2 aids in water absorption in intestinal epithelia. (Poroca, 2017)

Application of CLCN2 Membrane Protein in Literature

1. Haug K., et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat. Genet. 2005, 33(4):527-32. PubMed ID: 12612585
   
   

   The article identifies three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations can bring about (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations which are responsible for their pathogenic phenotypes.

2. Combi R., et al. Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy. Brain Res Bull. 2009, 79(2):89-96. PubMed ID: 19200853
   
   

   This article shows that two missense mutations in SCN1A are detected in two GEFS+ probands which confirms the importance of this channel for this epilepsy. What’s more, a previously unreported CLCN2 mutation is found in a proband showing CAE. The authors conclude that even in the highly heterogeneous cohort, the complexity of the epileptic condition is outstanding, while mutations in the analyzed candidate region of ion channel genes appear to explain only a minority of cases.

3. D'Agostino D., et al. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology. 2004, 63(8):1500-2. PubMed ID: 15505175
   
   

   The article analyzes the CLCN2 chloride channel gene in 112 probands with familial epilepsy, detecting 18 common polymorphisms. The results show us that CLCN2 mutations may be a rare cause of familial epilepsy and further studies are needed to test if polymorphisms in this gene are associated with epilepsy.

4. Hinzpeter A., et al. Association between Hsp90 and the ClC-2 chloride channel upregulates channel function. Am. J. Physiol., Cell Physiol. 2006, 108(6):2534-9. PubMed ID: 16049054
   
   

   This article shows that association between Hsp90 and ClC-2 results in greater channel activity by increasing cell surface channel expression, facilitation of channel opening, and enhanced channel sensitivity to intracellular [Cl⁻]. This association may also bring important pathophysiological consequences, which means that it can increase ClC-2 activity in response to cellular stresses such as elevated temperature, ischemia, or oxidative reagents.

5. Blaisdell C.J., et al. CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity BMC Med. Genet. 2004, 5:26. PubMed ID: 15507145
   
   

   This article suggests that there may not be a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene, and CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.

CLCN2 Preparation Options

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Reference

1. Poroca D R, et al. (2017). ClC channels and transporters: structure, physiological functions, and implications in human chloride channelopathies. Frontiers in pharmacology. 8, 151.

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