The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels.
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.
Dinudom
Anuwat
A
Department of Physiology, University of Sydney, Sydney NSW 2006, Australia.
Fotia
Andrew B
AB
Lefkowitz
Robert J
RJ
Young
John A
JA
Kumar
Sharad
S
Cook
David I
DI
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D056827:Endosomal Sorting Complexes Required for Transport; D004847:Epithelial Cells / Q000378:metabolism*; D025461:Feedback, Physiological; D006973:Hypertension / Q000209:etiology; D008297:Male; D051379:Mice; D008956:Models, Chemical; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled; D018987:Salivary Ducts / Q000166:cytology; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases
D056827:Endosomal Sorting Complexes Required for Transport; D043562:Receptors, G-Protein-Coupled; D062687:Sodium Channel Agonists; D015222:Sodium Channels; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases