AJP - Renal Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol (April 5, 2005). doi:10.1152/ajprenal.00394.2004
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/2/F334    most recent
00394.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Itani, O. A.
Right arrow Articles by Thomas, C. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Itani, O. A.
Right arrow Articles by Thomas, C. P.
Submitted on October 28, 2004
Accepted on March 29, 2005

Nedd4-2 isoforms differentially associate with ENaC and regulate its activity

Omar A. Itani1, John B. Stokes2, and Christie P. Thomas3*

1 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA, USA
2 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA
3 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA

* To whom correspondence should be addressed. E-mail: christie-thomas{at}uiowa.edu.

Mutations that disrupt a PY motif in epithelial Na+ channel (ENaC) subunits increase surface expression of Na+ channels in the collecting duct, resulting in greater Na+ reabsorption. Nedd4 and Nedd4-2 have been identified as ubiquitin ligases that can interact with ENaC via its PY motifs to regulate channel activity. We recently reported that human Nedd4-2 (hNedd4-2) is expressed as many isoforms due to alternative promoter usage and/or variable splicing. To understand the relevance of hNedd4-2 isoforms for collecting duct Na+ transport, we studied the interaction with ENaC, the intracellular localization and function of three naturally occurring hNedd4-2 isoforms: full length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the N-terminal C2 domain (Nedd4-2{Delta}C2) and Nedd4-2 lacking the C2 domain and WW domains 2 and 3 (Nedd4-2{Delta}WW2,3). Nedd4-2 and Nedd4-2{Delta}C2 associate with ENaC and robustly reduce Na+ transport in Xenopus oocytes, while the interaction with and functional effect of Nedd4- 2{Delta}WW2,3 on ENaC is weak. Nedd4-2 is expressed in the mouse collecting duct and overexpression of Nedd4-2 reduces endogenous ENaC activity in a collecting duct cell line. This reduction in ENaC activity can be reversed early with exposure to dexamethasone, an effect that is associated with an increase in sgk1 abundance. The C2 domain is required to target Nedd4-2 to the plasma membrane in response to elevation of intracellular calcium concentration ([Ca2+]i) in MDCK cells, though it does not appear to mediate the inhibitory effect of [Ca2+]i on Na+ transport. Our data illustrate that naturally occurring hNedd4-2 isoforms differentially associate with ENaC to regulate its activity.




This article has been cited by other articles:


Home page
 HypertensionHome page
F. Luo, Y. Wang, X. Wang, K. Sun, X. Zhou, and R. Hui
A Functional Variant of NEDD4L Is Associated With Hypertension, Antihypertensive Response, and Orthostatic Hypotension
Hypertension, October 1, 2009; 54(4): 796 - 801.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
N. S. Raikwar, P. M. Snyder, and C. P. Thomas
An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function
Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1440 - F1448.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
H.-Y. Chung, E. Morita, U. von Schwedler, B. Muller, H.-G. Krausslich, and W. I. Sundquist
NEDD4L Overexpression Rescues the Release and Infectivity of Human Immunodeficiency Virus Type 1 Constructs Lacking PTAP and YPXL Late Domains
J. Virol., May 15, 2008; 82(10): 4884 - 4897.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
N. S. Raikwar and C. P. Thomas
Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel
Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1157 - F1165.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
N. Araki, M. Umemura, Y. Miyagi, M. Yabana, Y. Miki, K. Tamura, K. Uchino, R. Aoki, Y. Goshima, S. Umemura, et al.
Expression, Transcription, and Possible Antagonistic Interaction of the Human Nedd4L Gene Variant: Implications for Essential Hypertension
Hypertension, March 1, 2008; 51(3): 773 - 777.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
O. Staub and F. Verrey
Impact of Nedd4 Proteins and Serum and Glucocorticoid-Induced Kinases on Epithelial Na+ Transport in the Distal Nephron
J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3167 - 3174.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 1977 by the American Physiological Society.