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J Biol Chem. 2015 Jan 2;290(1):568-76. doi: 10.1074/jbc.M114.606152. Epub 2014 Nov 11.

Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.

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From the Departments of Medicine and
From the Departments of Medicine and.
From the Departments of Medicine and Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.


The epithelial Na(+) channel (ENaC) has a key role in the regulation of extracellular fluid volume and blood pressure. ENaC belongs to a family of ion channels that sense the external environment. These channels have large extracellular regions that are thought to interact with environmental cues, such as Na(+), Cl(-), protons, proteases, and shear stress, which modulate gating behavior. We sought to determine the molecular mechanism by which ENaC senses high external Na(+) concentrations, resulting in an inhibition of channel activity. Both our structural model of an ENaC α subunit and the resolved structure of an acid-sensing ion channel (ASIC1) have conserved acidic pockets in the periphery of the extracellular region of the channel. We hypothesized that these acidic pockets host inhibitory allosteric Na(+) binding sites. Through site-directed mutagenesis targeting the acidic pocket, we modified the inhibitory response to external Na(+). Mutations at selected sites altered the cation inhibitory preference to favor Li(+) or K(+) rather than Na(+). Channel activity was reduced in response to restraining movement within this region by cross-linking structures across the acidic pocket. Our results suggest that residues within the acidic pocket form an allosteric effector binding site for Na(+). Our study supports the hypothesis that an acidic cleft is a key ligand binding locus for ENaC and perhaps other members of the ENaC/degenerin family.


Acid-sensing Ion Channel (ASIC); Allosteric Regulation; Effector Specificity; Epithelial Sodium Channel (ENaC); Hypertension; Ion Channel; Membrane Transport; Protein Cross-linking; pH-dependent Activation

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