OR25-6 Non-canonical control of vasopressin receptor type 2 signaling by retromer and arrestin

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR25-Signaling Originating from Membrane Receptors
Basic/Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 133 (Moscone Center)
Timothy N Feinstein*1, Naofumi Yui2, Matthew J. Webber3, Hilary P Stevenson1, J Darwin King1, Kenneth J Hallows4, Dennis Brown2, Richard Bouley5 and Jean-Pierre Vilardaga1
1University of Pittsburgh, Pittsburgh, PA, 2Massachusetts General Hospital and Harvard Medical School, Boston, MA, 3Center for Systems Biology, Program in Membrane Biology and Nephrology Division, Department of Medicine, Boston, MA, 4University of Pittsburgh, School of Medicine, Pittsburgh, PA, 5Massachusett General Hospital, Boston, MA
The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes.  Contrary to classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP­V2R complex yet extend rather than shorten the generation of cAMP.  Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na+ transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor (PTHR), these data support the existence of a novel “non-canonical” regulatory pathway for GPCR activation and response termination, via the sequential action of b-arrestin and the retromer complex.

Nothing to Disclose: TNF, NY, MJW, HPS, JDK, KJH, DB, RB, JPV

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grants: DK087688, DK38452, DK96586, DK075048, DK57521, DK43341
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