Modulation of epithelial sodium channel trafficking and function by sodium 4-phenylbutyrate in human nasal epithelial cells.

Abstract

Sodium 4-phenylbutyrate (4-PBA) has been shown to correct the cellular trafficking of several mutant or nonmutant plasma membrane proteins such as cystic fibrosis transmembrane conductance regulator through the expression of 70-kDa heat shock proteins. The objective of the study was to determine whether 4-PBA may influence the functional expression of epithelial sodium channels (ENaC) in human nasal epithelial cells (HNEC). Using primary cultures of HNEC, we demonstrate that 4-PBA (5 mm for 6 h) markedly stimulated amiloride-sensitive sodium channel activity and that this was related to an increased abundance of alpha-, beta-, and gamma-ENaC subunits in the apical membrane. The increase in ENaC cell surface expression (i) was due to insertion of newly ENaC subunits as determined by brefeldin A experiments and (ii) was not associated with cell surface retention of ENaC subunits because endocytosis of ENaC subunits was unchanged. In addition, we find that ENaC co-immunoprecipitated with the heat shock protein constitutively expressed Hsc70, that has been reported to modulate ENaC trafficking, and that 4-PBA decreased Hsc70 protein level. Finally, we report that in cystic fibrosis HNEC obtained from two cystic fibrosis patients, 4-PBA increased functional expression of ENaC as demonstrated by the increase in amiloride-sensitive sodium transport and in alpha-, beta-, and gamma-ENaC subunit expression in the apical membrane. Our results suggest that in HNEC, 4-PBA increases the functional expression of ENaC through the insertion of new alpha-, beta-, and gamma-ENaC subunits into the apical membrane and also suggest that 4-PBA could modify ENaC trafficking by reducing Hsc70 protein expression.

• Authors: Virginie Prulière-Escabasse, Carole Planès, Estelle Escudier, Pascale Fanen, André Coste, Christine Clerici
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 47 Pg. 34048-57 (Nov 23 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17890229 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HSC70 Heat-Shock Proteins
• HSPA8 protein, human
• Phenylbutyrates
• Protein Subunits
• Protein Synthesis Inhibitors
• Sodium Channels
• Cystic Fibrosis Transmembrane Conductance Regulator
• Brefeldin A
• 4-phenylbutyric acid

Topics

• Antineoplastic Agents (pharmacology)
• Brefeldin A (pharmacology)
• Cell Membrane (metabolism, pathology)
• Cells, Cultured
• Cystic Fibrosis (metabolism, pathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Endocytosis (drug effects)
• Gene Expression Regulation
• HSC70 Heat-Shock Proteins (biosynthesis)
• Humans
• Nasal Mucosa (metabolism, pathology)
• Phenylbutyrates (pharmacology)
• Protein Subunits (metabolism)
• Protein Synthesis Inhibitors (pharmacology)
• Protein Transport (drug effects)
• Sodium Channels (metabolism)