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Insulin stimulation of the epithelial sodium channel is inhibited by COMMD1
Author(s) -
McDonald Fiona Jean,
Swart Marianne,
Ke Ying
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.611.13
Subject(s) - epithelial sodium channel , sgk1 , nedd4 , ubiquitin , amiloride , ubiquitin ligase , sodium channel , chemistry , endocrinology , medicine , hek 293 cells , downregulation and upregulation , distal convoluted tubule , biology , microbiology and biotechnology , kidney , phosphorylation , receptor , sodium , biochemistry , reabsorption , organic chemistry , gene
The epithelial sodium channel (ENaC) transports Na + into epithelial cells located in the distal nephron, lung, and colon. Active channel number at the cell surface is regulated by ubiquitin modification and endocytosis. Insulin, aldosterone and vasopressin enhance Na + transport via the serum and glucocorticoid regulated kinase (SGK1) that inactivates the ubiquitin ligase Nedd4‐2 that downregulates ENaC. Previously we reported that COMMD1 ( co pper m etabolism M urr1 domain containing protein 1) inhibits ENaC amiloride‐sensitive current. Here the objective was to determine if COMMD1 and ENaC are coexpressed in kidney, and to study the mechanism by which COMMD1 inhibits ENaC amiloride‐sensitive current. Using immunohistochemistry COMMD1 was found to be widely expressed in the kidney, and to co‐localise with ENaC. Biochemical and electrophysiological assays showed that COMMD1 increased ubiquitin modification of ENaC and decreased its cell surface expression. COMMD1 abolished insulin‐stimulated amiloride‐sensitive current. COMMD1 co‐immunoprecipitated with SGK1 and Akt1, but not Nedd4‐2. Knock‐down of COMMD1 enhanced the effect of SGK1 and Akt1 on amiloride‐sensitive current, but did not change the effect of Nedd4‐2. In conclusion, COMMD1 regulates ENaC cell surface expression via Nedd4‐2. Support from the Marsden Fund Council from Government funding administered by the Royal Society of New Zealand