Extracellular Chloride Regulates the Epithelial Sodium Channel*

AUTOR(ES)

Collier, Daniel M.

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

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 SO42−, H2PO4−, 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− < SO42− < H2PO4− < 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 (αH418A and βR388A) 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.

Documentos Relacionados

• Non-specific activation of the epithelial sodium channel by the CFTR chloride channel
• Drosomycin, an Innate Immunity Peptide of Drosophila melanogaster, Interacts with the Fly Voltage-gated Sodium Channel*
• In vivo phosphorylation of the epithelial sodium channel
• Triple N-Glycosylation in the Long S5-P Loop Regulates the Activation and Trafficking of the Kv12.2 Potassium Channel*
• Accessory factors and the regulation of epithelial sodium channel activity