Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Aug 13

PMID 23935101

Citations 95

Authors

Timothy N Feinstein

Naofumi Yui

Matthew J Webber

Vanessa L Wehbi

Hilary P Stevenson

J Darwin King Jr

Kenneth R Hallows

Dennis Brown

Richard Bouley

Jean-Pierre Vilardaga

Affiliations

Soon will be listed here.

Abstract

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 the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R 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, these data support the existence of a novel "noncanonical" regulatory pathway for GPCR activation and response termination, via the sequential action of β-arrestin and the retromer complex.

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