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J Biol Chem
2011 Aug 05;28631:27436-46. doi: 10.1074/jbc.M111.232058.
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External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains.
Chen J, Myerburg MM, Passero CJ, Winarski KL, Sheng S.
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Epithelial Na(+) channels (ENaCs) play an essential role in the regulation of body fluid homeostasis. Certain transition metals activate or inhibit the activity of ENaCs. In this study, we examined the effect of extracellular Cu(2+) on human ENaC expressed in Xenopus oocytes and investigated the structural basis for its effects. External Cu(2+) inhibited human αβγ ENaC with an estimated IC(50) of 0.3 μM. The slow time course and a lack of change in the current-voltage relationship were consistent with an allosteric (non pore-plugging) inhibition of human ENaC by Cu(2+). Experiments with mixed human and mouse ENaC subunits suggested that both the α and β subunits were primarily responsible for the inhibitory effect of Cu(2+) on human ENaC. Lowering bath solution pH diminished the inhibition by Cu(2+). Mutations of two α, two β, and two γ His residues within extracellular domains significantly reduced the inhibition of human ENaC by Cu(2+). We identified a pair of residues as potential Cu(2+)-binding sites at the subunit interface between thumb subdomain of αhENaC and palm subdomain of βhENaC, suggesting a counterclockwise arrangement of α, β, and γ ENaC subunits in a trimeric channel complex when viewed from above. We conclude that extracellular Cu(2+) is a potent inhibitor of human ENaC and binds to multiple sites within the extracellular domains including a subunit interface.
Adamson,
Pulmonary toxicity of an atmospheric particulate sample is due to the soluble fraction.
1999, Pubmed
Adamson,
Pulmonary toxicity of an atmospheric particulate sample is due to the soluble fraction.
1999,
Pubmed Askwith,
DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature.
2001,
Pubmed
,
Xenbase Barlow,
Ion-pairs in proteins.
1983,
Pubmed Bhalla,
Mechanisms of ENaC regulation and clinical implications.
2008,
Pubmed Bruns,
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit.
2007,
Pubmed
,
Xenbase Carattino,
Epithelial Na+ channels are activated by laminar shear stress.
2004,
Pubmed
,
Xenbase Carattino,
The epithelial Na+ channel is inhibited by a peptide derived from proteolytic processing of its alpha subunit.
2006,
Pubmed
,
Xenbase Chalfant,
Intracellular H+ regulates the alpha-subunit of ENaC, the epithelial Na+ channel.
1999,
Pubmed
,
Xenbase Chraïbi,
Na self inhibition of human epithelial Na channel: temperature dependence and effect of extracellular proteases.
2002,
Pubmed
,
Xenbase Collier,
Extracellular chloride regulates the epithelial sodium channel.
2009,
Pubmed
,
Xenbase Collier,
Identification of epithelial Na+ channel (ENaC) intersubunit Cl- inhibitory residues suggests a trimeric alpha gamma beta channel architecture.
2011,
Pubmed
,
Xenbase Collier,
Extracellular protons regulate human ENaC by modulating Na+ self-inhibition.
2009,
Pubmed
,
Xenbase Davis,
Epithelial sodium channels in the adult lung--important modulators of pulmonary health and disease.
2007,
Pubmed Dokmanić,
Metals in proteins: correlation between the metal-ion type, coordination number and the amino-acid residues involved in the coordination.
2008,
Pubmed Donaldson,
Sodium channels and cystic fibrosis.
2007,
Pubmed Garty,
Epithelial sodium channels: function, structure, and regulation.
1997,
Pubmed Gonzales,
Pore architecture and ion sites in acid-sensing ion channels and P2X receptors.
2009,
Pubmed Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed Karlsson,
Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes.
2008,
Pubmed Kellenberger,
Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase Kiss,
Toxic effects of heavy metals on ionic channels.
1994,
Pubmed Kleyman,
ENaC at the cutting edge: regulation of epithelial sodium channels by proteases.
2009,
Pubmed Maarouf,
Novel determinants of epithelial sodium channel gating within extracellular thumb domains.
2009,
Pubmed
,
Xenbase McDonald,
Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel.
1995,
Pubmed
,
Xenbase McDonald,
Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel.
1994,
Pubmed
,
Xenbase Myerburg,
Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking.
2010,
Pubmed Nagaya,
An intersubunit zinc binding site in rat P2X2 receptors.
2005,
Pubmed
,
Xenbase Nevin,
Insights into the structural basis for zinc inhibition of the glycine receptor.
2003,
Pubmed Nie,
8-pCPT-cGMP stimulates alphabetagamma-ENaC activity in oocytes as an external ligand requiring specific nucleotide moieties.
2010,
Pubmed
,
Xenbase Pace,
Protein ionizable groups: pK values and their contribution to protein stability and solubility.
2009,
Pubmed Passero,
New role for plasmin in sodium homeostasis.
2010,
Pubmed Prieditis,
Comparative pulmonary toxicity of various soluble metals found in urban particulate dusts.
2002,
Pubmed Restrepo-Angulo,
Ion channels in toxicology.
2010,
Pubmed Rossier,
Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors.
2002,
Pubmed Rulísek,
Coordination geometries of selected transition metal ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in metalloproteins.
1998,
Pubmed Sheng,
Extracellular histidine residues crucial for Na+ self-inhibition of epithelial Na+ channels.
2004,
Pubmed
,
Xenbase Sheng,
External nickel inhibits epithelial sodium channel by binding to histidine residues within the extracellular domains of alpha and gamma subunits and reducing channel open probability.
2002,
Pubmed
,
Xenbase Sheng,
Functional role of extracellular loop cysteine residues of the epithelial Na+ channel in Na+ self-inhibition.
2007,
Pubmed
,
Xenbase Sheng,
Extracellular Zn2+ activates epithelial Na+ channels by eliminating Na+ self-inhibition.
2004,
Pubmed
,
Xenbase Sheng,
Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition.
2006,
Pubmed
,
Xenbase Tisato,
Copper in diseases and treatments, and copper-based anticancer strategies.
2010,
Pubmed Van Driessche,
Ionic channels in epithelial cell membranes.
1985,
Pubmed Volk,
Extracellular Na+ removal attenuates rundown of the epithelial Na+-channel (ENaC) by reducing the rate of channel retrieval.
2004,
Pubmed
,
Xenbase Yu,
Effect of divalent heavy metals on epithelial Na+ channels in A6 cells.
2007,
Pubmed
,
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