CLC chloride channels and transporters.

Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20246 Hamburg.
Current Opinion in Neurobiology (Impact Factor: 6.77). 07/2005; 15(3):319-25. DOI: 10.1016/j.conb.2005.05.002
Source: PubMed

ABSTRACT CLC proteins are found in cells from prokaryotes to mammals and perform functions in plasma membranes and intracellular vesicles. Several genetic human diseases and mouse models underscore their broad physiological functions in mammals. These functions range from the control of excitability to transepithelial transport, endocytotic trafficking and acidification of synaptic vesicles. The recent crystallization of bacterial CLC proteins gave surprising insights into CLC Cl(-)-channel permeation and gating and provides an excellent basis for structure-function studies. Surprisingly, the CLC from Escherichia coli functions as a Cl-/H+ exchanger, thus demonstrating the thin line separating transporters and channels.

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    ABSTRACT: The ClC-type proteins, a large family of chloride transport proteins ubiquitously expressed in biological organisms, have been extensively studied for decades. Biological function of ClC proteins can be reflected by analyzing the binding situation of Cl− ions. We investigate ion binding properties of ClC-ec1 protein with the atomic molecular dynamics simulation approach. The calculated electrostatic binding energy results indicate that Cl− at the central binding site Scen has more binding stability than the internal binding site Sint. Quantitative comparison between the latest experimental heat release data isothermal titration calorimetry (ITC) and our calculated results demonstrates that chloride ions prefer to bind at Scen than Sint in the wild-type ClC-ec1 structure and prefer to bind at Sext and Scen than Sint in mutant E148A/E148Q structures. Even though the chloride ions make less contribution to heat release when binding to Sint and are relatively unstable in the Cl− pathway, they are still part contributors for the Cl− functional transport. This work provides a guide rule to estimate the importance of Cl− at the binding sites and how chloride ions have influences on the function of ClC proteins.
    Chinese Physics Letters 06/2014; 31(6):068701. DOI:10.1088/0256-307X/31/6/068701 · 0.92 Impact Factor
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    ABSTRACT: CLC-K chloride channels and their subunit, barttin, are crucial for renal NaCl reabsorption and for inner ear endolymph production. Mutations in CLC-Kb and barttin cause Bartter syndrome. Here, we identified two adjacent residues, F256 and N257, that when mutated hugely alter in Xenopus oocytes CLC-Ka's biphasic response to niflumic acid, a drug belonging to the fenamate class, with F256A being potentiated 37-fold and N257A being potently blocked with a KD~1μM. These residues are localized in the same extracellular I-J loop which harbors a regulatory Ca(2+) binding site. This loop thus can represent an ideal and CLC-K specific target for extracellular ligands able to modulate channel activity. Furthermore, we demonstrated the involvement of the barttin subunit in the NFA potentiation. Indeed the F256A mutation confers onto CLC-K1 a transient potentiation induced by NFA which is found only when CLC-K1/F256A is co-expressed with barttin. Thus, in addition to the role of barttin in targeting and gating, the subunit participates in the pharmacological modulation of CLC-K channels and thus represents a further target for potential drugs.
    Biochimica et Biophysica Acta (BBA) - Biomembranes 07/2014; 1838(11). DOI:10.1016/j.bbamem.2014.07.021 · 3.43 Impact Factor
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    ABSTRACT: Excessive chloride electrolyte infusion is responsible for metabolic hyperchloremic acidosis. It is related to infusion of isotonic saline solutions, leading cause of metabolic acidosis in intensive care patients. Hyperchloremia is also associated with haemostasis disturbances, inflammatory status, an increased risk of renal failure and mortality in intensive care patients. Balanced saline solutions should be used preferably.
    Le Praticien en Anesthésie Réanimation 10/2014; DOI:10.1016/j.pratan.2014.08.007

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