Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2

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dc.contributor.authorLee, I.
dc.contributor.authorDinudom, A.
dc.contributor.authorSanchez-Perez, A.
dc.contributor.authorKumar, S.
dc.contributor.authorCook, D.
dc.date.issued2007
dc.description.abstractThe epithelial sodium channel (ENaC) plays an important role in transepithelial Na+ absorption; hence its function is essential for maintaining Na+ and fluid homeostasis and regulating blood pressure. Insulin is one of the hormones that regulates activity of ENaC. In this study, we investigated the contribution of two related protein kinases, Akt (also known as protein kinase B) and the serum- and glucocorticoid-dependent kinase (Sgk), on insulin-induced ENaC activity in Fisher rat thyroid cells expressing ENaC. Overexpression of Akt1 or Sgk1 significantly increased ENaC activity, whereas expression of a dominant-negative construct of Akt1, Akt1K179M, decreased basal activity of ENaC. Inhibition of the endogenous expression of Akt1 and Sgk1 by short interfering RNA not only inhibited ENaC but also disrupted the stimulatory effect on ENaC of insulin and of the downstream effectors of insulin, phosphatidylinositol 3-kinase and PDK1. Conversely, overexpression of Akt1 or Sgk1 increased expression of ENaC at the cell membrane and overcame the inhibitory effect of Nedd4-2 on ENaC. Furthermore, mutation of consensus phosphorylation sites on Nedd4-2 for Akt1 and Sgk1, Ser342 and Ser428, completely abolished the inhibitory effect of Sgk1 and Akt1 on Nedd4-2 action. Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na+ absorption by up-regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2.
dc.description.statementofresponsibilityIl-Ha Lee, Anuwat Dinudom, Angeles Sanchez-Perez, Sharad Kumar and David I. Cook
dc.identifier.citationJournal of Biological Chemistry, 2007; 282(41):29866-29873
dc.identifier.doi10.1074/jbc.M701923200
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.urihttp://hdl.handle.net/2440/60354
dc.language.isoen
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.rights© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.source.urihttps://doi.org/10.1074/jbc.m701923200
dc.subjectCell Membrane
dc.subjectAnimals
dc.subjectMice
dc.subjectRats
dc.subjectInsulin
dc.subjectUbiquitin-Protein Ligases
dc.subjectImmediate-Early Proteins
dc.subjectRNA, Small Interfering
dc.subjectGlucocorticoids
dc.subjectElectrophysiology
dc.subjectGene Expression Regulation
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectEndosomal Sorting Complexes Required for Transport
dc.subjectEpithelial Sodium Channels
dc.subjectNedd4 Ubiquitin Protein Ligases
dc.subjectProtein Serine-Threonine Kinases
dc.titleAkt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2
dc.typeJournal article
pubs.publication-statusPublished

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