The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels.

Journal Article (Journal Article)

Epithelial Na(+) channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, with loss of this inhibition leading to hypertension. Here, we report that these channels are maintained in the active state by the G protein-coupled receptor kinase, Grk2, which has been previously implicated in the development of essential hypertension. We also show that Grk2 phosphorylates the C terminus of the channel beta subunit and renders the channels insensitive to inhibition by Nedd4-2. This mechanism has not been previously reported to regulate epithelial Na(+) channels and provides a potential explanation for the observed association of Grk2 overactivity with hypertension. Here, we report a G protein-coupled receptor kinase regulating a membrane protein other than a receptor and provide a paradigm for understanding how the interaction between membrane proteins and ubiquitin protein ligases is controlled.

Full Text

Duke Authors

Cited Authors

  • Dinudom, A; Fotia, AB; Lefkowitz, RJ; Young, JA; Kumar, S; Cook, DI

Published Date

  • August 10, 2004

Published In

Volume / Issue

  • 101 / 32

Start / End Page

  • 11886 - 11890

PubMed ID

  • 15284439

Pubmed Central ID

  • PMC511069

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0402178101


  • eng

Conference Location

  • United States