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A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes

Harris, Michael ; Firsov, Dmitri ; Vuagniaux, Grégoire ; Stutts, M. Jackson ; Rossier, Bernard C.

The Journal of biological chemistry, 2007-01, Vol.282 (1), p.58-64 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes
Autor: Harris, Michael ; Firsov, Dmitri ; Vuagniaux, Grégoire ; Stutts, M. Jackson ; Rossier, Bernard C.
Assuntos: Animals ; Cell Membrane - metabolism ; Enzyme Activation ; Enzyme Inhibitors - chemistry ; Epithelial Sodium Channels - metabolism ; Epithelial Sodium Channels - physiology ; Freshwater ; Leukocyte Elastase - antagonists & inhibitors ; Oocytes - metabolism ; Peptides - chemistry ; Peptides - pharmacology ; Protein Engineering ; RNA, Complementary - metabolism ; Serine Endopeptidases - chemistry ; Surface Properties ; Trypsin - chemistry ; Xenopus laevis
É parte de: The Journal of biological chemistry, 2007-01, Vol.282 (1), p.58-64
Notas: http://www.jbc.org/
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Descrição: The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a limiting step in sodium reabsorption across distal airway epithelium and controlling mucociliary clearance. ENaC is activated by serine proteases secreted in the extracellular milieu. In cystic fibrosis lungs, high concentrations of secreted neutrophil elastase (NE) are observed. hNE could activate ENaC and contribute to further decreased mucociliary clearance. The aims of this study were (i) to test the ability of an engineered human neutrophil elastase inhibitor (EPI-hNE4) to specifically inhibit the elastase activation of ENaC-mediated amiloride-sensitive currents (INa) and (ii) to examine the effect of elastase on cell surface expression of ENaC and its cleavage pattern (exogenous proteolysis). Oocytes were exposed to hNE (10–100 μg/ml) and/or trypsin (10 μg/ml) for 2–5 min in the presence or absence of EPI-hNE4 (0.7 μm). hNE activated INa 3.6-fold (p < 0.001) relative to non-treated hENaC-injected oocytes. EPI-hNE4 fully inhibited hNE-activated INa but had no effect on trypsin- or prostasin-activated INa. The co-activation of INa by hNE and trypsin was not additive. Biotinylation experiments revealed that cell surface γ ENaC (but not α or β ENaC) exposed to hNE for 2 min was cleaved (as a 67-kDa fragment) and correlated with increased INa. The elastase-induced exogenous proteolysis pattern is distinct from the endogenous proteolysis pattern induced upon preferential assembly, suggesting a causal relationship between γ ENaC cleavage and ENaC activation, taking place at the plasma membrane.
Editor: United States: Elsevier Inc
Idioma: Inglês

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A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes

Harris, Michael ; Firsov, Dmitri ; Vuagniaux, Grégoire ; Stutts, M. Jackson ; Rossier, Bernard C.

United States: Elsevier Inc

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