http://www.cnr.it/ontology/cnr/individuo/prodotto/ID277882

A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter (Articolo in rivista)

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A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter (Articolo in rivista) (literal)

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De Stefano S, Pusch M, Zifarelli G (2013)
A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter
in Journal of physiology (Lond., Print); WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ (Stati Uniti d'America)
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Titolo

A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter (literal)

Abstract

ClC-5 is a 2Cl-/1H+ antiporter highly expressed in endosomes of proximal tubule cells. It is essential for endocytosis and mutations in ClC-5 cause Dent's disease, potentially leading to renal failure. However, the physiological role of ClC-5 is still unclear. One of the main issues is whether the strong rectification of ClC-5 currents observed in heterologous systems, with currents elicited only at positive voltages, is preserved in vivo and what is the origin of this rectification. In this work we identified a ClC-5 mutation, D76H, which, besides the typical outward currents of the wild-type (WT), shows inward tail currents at negative potentials that allow the estimation of the reversal of ClC-5 currents for the first time. A detailed analysis of the dependence of these inward tail currents on internal and external pH and [Cl-] shows that they are generated by a coupled transport of Cl- and H+ with a 2 : 1 stoichiometry. From this result we conclude that the inward tail currents are caused by a gating mechanism that regulates ClC-5 transport activity and not by a major alteration of the transport mechanism itself. This implies that the strong rectification of the currents of WT ClC-5 is at least in part caused by a gating mechanism that activates the transporter at positive potentials. These results elucidate the biophysical properties of ClC-5 and contribute to the understanding of its physiological role (literal)

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