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

Omar A Itani1, John B Stokes, Christie P Thomas

  • 1Department of Internal Medicine, University of Iowa, Iowa City, 52242, USA.

American Journal of Physiology. Renal Physiology
|April 9, 2005
PubMed
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Different forms of human Nedd4-2 (hNedd4-2) regulate epithelial sodium channel (ENaC) activity. Full-length and C2-domain-deleted hNedd4-2 isoforms effectively reduce sodium transport, while other isoforms show weaker effects.

Area of Science:

  • Physiology
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in epithelial sodium channel (ENaC) increase sodium reabsorption in the collecting duct.
  • Nedd4 and Nedd4-2 are ubiquitin ligases that regulate ENaC activity through PY motifs.
  • Human Nedd4-2 (hNedd4-2) exists in multiple isoforms due to alternative promoter usage and splicing.

Purpose of the Study:

  • To investigate the functional relevance of different hNedd4-2 isoforms in regulating collecting duct sodium transport.
  • To compare the interaction, localization, and functional effects of three naturally occurring hNedd4-2 isoforms with ENaC.

Main Methods:

  • Studied interaction between ENaC and three hNedd4-2 isoforms (full-length, Nedd4-2DeltaC2, Nedd4-2DeltaWW2,3).
  • Assessed intracellular localization and function in Xenopus oocytes and MDCK cells.

Related Experiment Videos

  • Examined ENaC activity in mouse collecting duct and cell lines, including effects of dexamethasone and intracellular calcium.

    • Main Results:

    • Nedd4-2 and Nedd4-2DeltaC2 isoforms strongly associate with ENaC and reduce Na(+) transport in Xenopus oocytes.
    • Nedd4-2DeltaWW2,3 showed weak interaction and functional effect on ENaC.
    • Overexpression of Nedd4-2 reduced endogenous ENaC activity in a collecting duct cell line, an effect reversible by dexamethasone.
    • The C2 domain targets Nedd4-2 to the plasma membrane in response to increased intracellular calcium, but does not mediate the inhibitory effect of calcium on Na(+) transport.

    Conclusions:

    • Naturally occurring hNedd4-2 isoforms differentially interact with ENaC, leading to varied regulation of its activity.
    • Isoform-specific interactions of Nedd4-2 with ENaC are crucial for controlling sodium transport in the collecting duct.