ArticleThe Journal of biological chemistry2012
Probing the structural basis of Zn2+ regulation of the epithelial Na+ channel.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Structural insights into subunit-dependent functional regulation in epithelial sodium channels.Structure (London, England : 1993) · 2025Article
- Epithelial NaComprehensive Physiology · 2024Review
- Physiological insight into the conserved properties of Caenorhabditis elegans acid-sensing degenerin/epithelial sodium channels.The Journal of physiology · 2023Article
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- New insights regarding epithelial Na+ channel regulation and its role in the kidney, immune system and vasculature.Current opinion in nephrology and hypertension · 2019Review
- Thumb domains of the three epithelial NaThe Journal of biological chemistry · 2018Article
- The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations.American journal of respiratory cell and molecular biology · 2017Article
- Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins.International journal of molecular sciences · 2016Review
- Deletion of α-subunit exon 11 of the epithelial Na+ channel reveals a regulatory module.American journal of physiology. Renal physiology · 2014Article
- Article
- Extracellular zinc ion regulates transient receptor potential melastatin 5 (TRPM5) channel activation through its interaction with a pore loop domain.The Journal of biological chemistry · 2013Article
- Gain-of-function variant of the human epithelial sodium channel.American journal of physiology. Renal physiology · 2013Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Extracellular Zn(2+) activates the epithelial Na(+) channel (ENaC) by relieving Na(+) self-inhibition. However, a biphasic Zn(2+) dose response was observed, suggesting that Zn(2+) has dual effects on the channel (i.e. activating and inhibitory). To investigate the structural basis for this biphasic effect of Zn(2+), we examined the effects of mutating the 10 extracellular His residues of mouse γENaC. Four mutations within the finger subdomain (γH193A, γH200A, γH202A, and γH239A) significantly reduced the maximal Zn(2+) activation of the channel. Whereas γH193A, γH200A, and γH202A reduced the apparent affinity of the Zn(2+) activating site, γH239A diminished Na(+) self-inhibition and thus concealed the activating effects of Zn(2+). Mutation of a His residue within the palm subdomain (γH88A) abolished the low-affinity Zn(2+) inhibitory effect. Based on structural homology with acid-sensing ion channel 1, γAsp(516) was predicted to be in close proximity to γHis(88). Ala substitution of the residue (γD516A) blunted the inhibitory effect of Zn(2+). Our results suggest that external Zn(2+) regulates ENaC activity by binding to multiple extracellular sites within the γ-subunit, including (i) a high-affinity stimulatory site within the finger subdomain involving His(193), His(200), and His(202) and (ii) a low-affinity Zn(2+) inhibitory site within the palm subdomain that includes His(88) and Asp(516).
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