Document Detail

Preferential assembly of epithelial sodium channel (ENaC) subunits in Xenopus oocytes: role of furin-mediated endogenous proteolysis.
MedLine Citation:
PMID:  18195015     Owner:  NLM     Status:  MEDLINE    
The epithelial sodium channel (ENaC) is preferentially assembled into heteromeric alphabetagamma complexes. The alpha and gamma (not beta) subunits undergo proteolytic cleavage by endogenous furin-like activity correlating with increased ENaC function. We identified full-length subunits and their fragments at the cell surface, as well as in the intracellular pool, for all homo- and heteromeric combinations (alpha, beta, gamma, alphabeta, alphagamma, betagamma, and alphabetagamma). We assayed corresponding channel function as amiloride-sensitive sodium transport (I(Na)). We varied furin-mediated proteolysis by mutating the P1 site in alpha and/or gamma subunit furin consensus cleavage sites (alpha(mut) and gamma(mut)). Our findings were as follows. (i) The beta subunit alone is not transported to the cell surface nor cleaved upon assembly with the alpha and/or gamma subunits. (ii) The alpha subunit alone (or in combination with beta and/or gamma) is efficiently transported to the cell surface; a surface-expressed 65-kDa alpha ENaC fragment is undetected in alpha(mut)betagamma, and I(Na) is decreased by 60%. (iii) The gamma subunit alone does not appear at the cell surface; gamma co-expressed with alpha reaches the surface but is not detectably cleaved; and gamma in alphabetagamma complexes appears mainly as a 76-kDa species in the surface pool. Although basal I(Na) of alphabetagamma(mut) was similar to alphabetagamma, gamma(mut) was not detectably cleaved at the cell surface. Thus, furin-mediated cleavage is not essential for participation of alpha and gamma in alphabetagamma heteromers. Basal I(Na) is reduced by preventing furin-mediated cleavage of the alpha, but not gamma, subunits. Residual current in the absence of furin-mediated proteolysis may be due to non-furin endogenous proteases.
Michael Harris; Agustin Garcia-Caballero; M Jackson Stutts; Dmitri Firsov; Bernard C Rossier
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-01-14
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-17     Completed Date:  2008-05-12     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7455-63     Citation Subset:  IM    
Département de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland.
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MeSH Terms
Amiloride / pharmacology
Cell Membrane / genetics,  metabolism*
Epithelial Sodium Channels / genetics,  metabolism*
Furin / genetics,  metabolism*
Ion Transport / drug effects
Oocytes / cytology,  metabolism*
Protein Processing, Post-Translational / physiology*
Protein Structure, Quaternary / physiology
Protein Subunits / genetics,  metabolism
Sodium / metabolism
Sodium Channel Blockers / pharmacology
Xenopus laevis
Grant Support
Reg. No./Substance:
0/Epithelial Sodium Channels; 0/Protein Subunits; 0/Sodium Channel Blockers; 2609-46-3/Amiloride; 7440-23-5/Sodium; EC

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