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Extracellular Chloride Regulates the Epithelial Sodium Channel
Journal article   Open access   Peer reviewed

Extracellular Chloride Regulates the Epithelial Sodium Channel

Daniel M Collier and Peter M Snyder
The Journal of biological chemistry, Vol.284(43), pp.29320-29325
10/23/2009
DOI: 10.1074/jbc.M109.046771
PMCID: PMC2785562
PMID: 19713212
url
https://doi.org/10.1074/jbc.M109.046771View
Published (Version of record) Open Access

Abstract

The extracellular domain of the epithelial sodium channel ENaC is exposed to a wide range of Cl − concentrations in the kidney and in other epithelia. We tested whether Cl − alters ENaC activity. In Xenopus oocytes expressing human ENaC, replacement of Cl − with SO 4 2− , H 2 PO 4 − , or SCN − produced a large increase in ENaC current, indicating that extracellular Cl − inhibits ENaC. Extracellular Cl − also inhibited ENaC in Na + -transporting epithelia. The anion selectivity sequence was SCN − < SO 4 2− < H 2 PO 4 − < F − < I − < Cl − < Br − . Crystallization of ASIC1a revealed a Cl − binding site in the extracellular domain. We found that mutation of corresponding residues in ENaC (α H418A and β R388A ) disrupted the response to Cl − , suggesting that Cl − might regulate ENaC through an analogous binding site. Maneuvers that lock ENaC in an open state (a DEG mutation and trypsin) abolished ENaC regulation by Cl − . The response to Cl − was also modulated by changes in extracellular pH; acidic pH increased and alkaline pH reduced ENaC inhibition by Cl − . Cl − regulated ENaC activity in part through enhanced Na + self-inhibition, a process by which extracellular Na + inhibits ENaC. Together, the data indicate that extracellular Cl − regulates ENaC activity, providing a potential mechanism by which changes in extracellular Cl − might modulate epithelial Na + absorption.
 Membrane Transport, Structure, Function, and Biogenesis

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