CLCN5 Membrane Protein Introduction

Introduction of CLCN5

H(+)/Cl(-) exchange transporter 5 (CLCN5) is a protein that in humans is encoded by the CLCN5 gene. The protein is a member of the ClC family of chloride ion channels and ion transporters. Mutations in the CLCN5 gene have been found in Dent's disease and renal tubular disorders complicated by nephrolithiasis. Although as a member of a family of chloride channels, the CLCN5 protein allows movement of protons in the opposite direction of Cl(-), thus it can function as an antiporter.

Function of CLCN5 Membrane Protein

H(+)/Cl(-) exchange transporter 5 (CLCN5) always functions as antiport system and exchanges chloride ions against protons. It plays a very important role in normal acidification of the endosome lumen, as well as in renal tubular function. The CLC channel family contains both chloride channels and proton-coupled anion transporters, and the later can exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels. CLCN5 involves many molecular and biological processes. It can regulate antiporter activity, ATP binding, and chloride channel activity. What’s more, it participates in identical protein binding and voltage-gated chloride channel. It also takes part in the process of excretion and ion transmembrane transport. Activation of the CLCN5 can participate in sensations such as pain, warmth, cold, taste pressure and vision through stimuli-sensing channels.

Application of CLCN5 Membrane Protein in Literature

1. Picollo A., et al. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature. 2005, 436(7049):420-3. PubMed ID: 16034421
   
   

   This article finds that when ClC-4 and ClC-5 are activated by positive voltages, they can carry a substantial amount of protons across the plasma membrane, which can be detected by measurements of pH close to the cell surface. Both of them are able to extrude protons against their electrochemical gradient, demonstrating secondary active transport. Cl^- and H⁺ transportation contributes equally to the total charge movement in CIC-5, which results in a raising possibility that the coupled Cl^-/H⁺ transport of ClC-4 and ClC-5 is of significant magnitude in vivo.

2. Piwon N., et al. ClC-5 Cl^--channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature. 2000, 408:369-73. PubMed ID: 11099045
   
   

   This article shows that lack of clcn5 gene can reduce apical proximal tubular endocytosis in mice and cause proteinuria further. It can affect receptor-mediated and fluid-phase endocytosis and slow down the internalization of the apical transporters NaPi-2 and NHE3.

3. Christensen E.I., et al. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. PNAS. 2003, 100 (14) 8472-8477. PubMed ID: 12815097
   
   

   This article suggests that loss of the renal endosome-associated chloride channel, ClC-5, strongly inhibits endocytosis of filtered proteins by kidney proximal tubular cells (PTC) in Dent's disease and knockout (KO) mice. Total contents of the rate-limiting endocytic catalysts, Rab5a and Rab7, are unaffected by the expression of ClC-5. In conclusion, impaired protein endocytosis caused by invalidation of ClC-5 primarily reflects a trafficking defect of megalin and cubilin in PTC.

4. Günther W., et al. The ClC-5 chloride channel knock-out mouse – an animal model for Dent's disease. Pflügers Archiv. 2003, 445(4):456-62. PubMed ID: 12548389
   
   

   This article shows that the defective endocytosis entails an increased luminal concentration of PTH and subsequent stimulation of apical PTH receptors, which can promote the endocytosis of the phosphate transporter NaPi and phosphaturia. It also results in up-regulation of proximal tubular alpha-hydroxylase, which influences the active form of vitamin D. It then shows us how the primary defect in endocytosis leads by secondarily turning calciotropic hormones to the tertiary symptoms hyperphosphaturia, hypercalciuria and kidney stones.

5. Hara-Chikuma M., et al. Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Biochemical and Biophysical Research Communications 2005, 329(3):941-46. PubMed ID: 5752747
   
   

   It has been reported that ClC-5 chloride channel deficiency causes proteinuria, hypercalciuria, and nephrolithiasis (Dent's disease). One of the proposed mechanisms is impaired endosomal acidification in proximal tubule caused by reduced chloride conductance. The results in this article provide direct evidence that ClC-5 involvement in acidification of early endosomes in proximal tubule under the direction of a chloride shunt mechanism.

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