Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition

Collier, Daniel M.; Snyder, Peter M.

doi:10.1074/jbc.m806954200

Cited by 84 publications

(102 citation statements)

References 38 publications

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“…Although modest acidification (to pH 6.5) did not alter channel activity (see below), lowering the extracellular pH from 7.4 to 4.7 stimulated currents by 44 Ϯ 3% (n ϭ 6, p Ͻ 0.05 using paired Student's t test). This is similar to the increase observed for human ENaC by lowering the pH from 7.4 to 6.5 (10). When currents are measured under voltage clamp conditions, currents decay over time.…”

Section: Methodssupporting

confidence: 66%

“…This allosteric inhibition, referred to as Na ϩ self-inhibition, reflects a low-affinity (tens of micromolar), pH-sensitive, nonvoltage-sensitive reduction in ENaC open probability (8 -13). This inhibitory effect is also cation-selective because both Na ϩ and Li ϩ inhibit the channel, whereas K ϩ has a modest inhibitory effect at best, and protons activate the channel (9,10). Second, an elevated intracellular Na ϩ concentration inhibits the channel over a slow time course (14,15).…”

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confidence: 99%

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Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

Kashlan

Blobner

Zuzek

et al. 2015

Journal of Biological Chemistry

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Section: Methodssupporting

confidence: 66%

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confidence: 99%

Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

Kashlan

Blobner

Zuzek

et al. 2015

Journal of Biological Chemistry

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“…2D). The addition of HOCl did not significantly alter the pH or the Cl Ϫ concentration of the medium, two variables shown to modulate ENaC activity in previous studies (40,41).…”

Section: Exposure Of Mice To CLmentioning

confidence: 98%

Inhibition of Lung Fluid Clearance and Epithelial Na+ Channels by Chlorine, Hypochlorous Acid, and Chloramines

Song¹,

Wei²,

Zhou³

et al. 2010

Journal of Biological Chemistry

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We investigated the mechanisms by which chlorine (Cl 2 ) and its reactive byproducts inhibit Na ؉ -dependent alveolar fluid clearance (AFC) in vivo and the activity of amiloridesensitive epithelial Na ؉ channels (ENaC) by measuring AFC in mice exposed to Cl 2 (0 -500 ppm for 30 min) and Na ؉ and amiloride-sensitive currents (I Na and I amil , respectively) across Xenopus oocytes expressing human ␣-, ␤-, and ␥-ENaC incubated with HOCl (1-2000 M). Both Cl 2 and HOCl-derived products decreased AFC in mice and whole cell and single channel I Na in a dose-dependent manner; these effects were counteracted by serine proteases. Mass spectrometry analysis of the oocyte recording medium identified organic chloramines formed by the interaction of HOCl with HEPES (used as an extracellular buffer). In addition, chloramines formed by the interaction of HOCl with taurine or glycine decreased I Na in a similar fashion. Preincubation of oocytes with serine proteases prevented the decrease of I Na by HOCl, whereas perfusion of oocytes with a synthetic 51-mer peptide corresponding to the putative furin and plasmin cleaving segment in the ␥-ENaC subunit restored the ability of HOCl to inhibit I Na . Finally, I Na of oocytes expressing wild type ␣-and ␥-ENaC and a mutant form of ␤ENaC (S520K), known to result in ENaC channels locked in the open position, were not altered by HOCl. We concluded that HOCl and its reactive intermediates (such as organic chloramines) inhibit ENaC by affecting channel gating, which could be relieved by proteases cleavage.The balance of fluid covering the respiratory and alveolar epithelia is determined in part by the ability of these cells to transport sodium (Na ϩ ) and chloride (Cl Ϫ ) ions in a vectorial fashion. Active Na ϩ reabsorption across lung epithelia requires the coordinated entry of Na ϩ ions through cation-and Na ϩ -selective amiloride-sensitive channels (ENaC) 5 located at the apical membranes, their extrusion across the basolateral membranes by the electrogenic Na ϩ -K ϩ -ATPase, and the passive movement of K ϩ ions through basolateral K ϩ channels. The entry of Na ϩ ions through apical pathways is thought to be the rate-limiting step in this process (1-3). To preserve neutrality, Cl Ϫ ions follow Na ϩ ions both through transcellular and paracellular pathways (4, 5). The coordinated movement of Na ϩ and Cl Ϫ ions creates an oncotic gradient favoring the absorption of alveolar fluid.Injury to either apical or basolateral pathways by partially reduced intermediates may lead to impairment of fluid reabsorption, which in turn may result in pulmonary edema, hypoxemia, and eventually death from respiratory failure (6 -9). One such specie is hypochlorous acid (HOCl) 6 , which may be generated either endogenously or exogenously. Millimolar concentrations of HOCl may be generated by activated neutrophils and eosinophils by the catalytic actions of neutrophil-and eosinophil-derived myeloperoxidases on chloride (Cl Ϫ ) and hydrogen peroxide (H 2 O 2 ) in close proximity of the apical and basolatera...

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“…This activation mechanism by an extracellular ion as a ligand is unusual as channel activation by ions is typically observed intracellularly. Only protons are also known to induce activity of the sodium channel ENaC from the extracellular side (34) apparently by relieving self-inhibition of the channel by Na ϩ (35). Protons also activate acid-sensing ion channels (36).…”

Section: Discussionmentioning

confidence: 99%

The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes

Silverman¹,

Vaccari

Locovei³

et al. 2009

Journal of Biological Chemistry

491

603

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The inflammasome is a multiprotein complex involved in innate immunity. Activation of the inflammasome causes the processing and release of the cytokines interleukins 1␤ and 18. In primary macrophages, potassium ion flux and the membrane channel pannexin 1 have been suggested to play roles in inflammasome activation. However, the molecular mechanism(s) governing inflammasome signaling remains poorly defined, and it is undetermined whether these mechanisms apply to the central nervous system. Here we show that high extracellular potassium opens pannexin channels leading to caspase-1 activation in primary neurons and astrocytes. The effect of K ؉ on pannexin 1 channels was independent of membrane potential, suggesting that stimulation of inflammasome signaling was mediated by an allosteric effect. The activation of the inflammasome by K Pannexin 1 is a vertebrate ortholog of the invertebrate innexin gap junction proteins (1), but it does not appear to form functional gap junctions in vivo. Instead pannexin 1 acts as a membrane channel that carries ions and signaling molecules between the cytoplasm and the extracellular space (2, 3). As such, it is a candidate ATP release channel in various cell types, including erythrocytes, astrocytes, bronchial epithelial cells, and taste cells. Various functional roles have been ascribed to pannexin 1 including local vascular perfusion control and propagation of intercellular calcium waves (4 -6). Recently pannexin 1 was also shown to form the large pore of the P2X7 purinergic receptor (7, 8). P2X7 plays a major role in inflammation, and its activation by extracellular ATP results in release of interleukin (IL) 2 -1␤ from macrophages, probably involving pannexin 1 as a signaling molecule (7).IL-1␤ production and maturation are tightly regulated by caspase-1 incorporated into large protein complexes termed inflammasomes (9 -11). The molecular composition of the inflammasome depends on the identity of the NOD-like receptor (NLR) family member serving as a scaffold protein in the complex (12). The members of the cytosolic NLR family appear to recognize conserved microbial and viral components termed pathogen-associated molecular patterns in intracellular compartments (13). The bipartite adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) bridges the interaction between NLR proteins and inflammatory caspases and plays a central role in the assembly of inflammasomes and the activation of caspase-1 in response to a broad range of pathogen-associated molecular patterns and intracellular pathogens (14). In addition, the inflammasome can be activated by danger-associated molecular patterns, molecules endogenous to the organism that signal stress or injury, including extracellular ATP acting at ionotropic P2X7 receptors, fibronectin, or monosodium urate crystals (15,16). Moreover it has been suggested that a rapid K ϩ efflux through ATP-activated P2X7 receptors induces inflammasome assembly (17)(18)(19)(20).Despite the recent advances in the understanding of a...

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Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition

Cited by 84 publications

References 38 publications

Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

Na+ Inhibits the Epithelial Na+ Channel by Binding to a Site in an Extracellular Acidic Cleft

Inhibition of Lung Fluid Clearance and Epithelial Na+ Channels by Chlorine, Hypochlorous Acid, and Chloramines

The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes

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