Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin.
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.
From the Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
Timothy N
TN
Feinstein
Naofumi
N
Yui
Matthew J
MJ
Webber
Vanessa L
VL
Wehbi
Hilary P
HP
Stevenson
J Darwin
JD
King
Kenneth R
KR
Hallows
Dennis
D
Brown
Richard
R
Bouley
Jean-Pierre
JP
Vilardaga
D000818:Animals; D050034:Antidiuretic Agents / Q000494:pharmacology; D051399:Aquaporin 2 / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D011992:Endosomes / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D010121:Oxytocin / Q000737:chemistry; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D000071557:beta-Arrestins
D050034:Antidiuretic Agents; D051399:Aquaporin 2; D019390:Arrestins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins; D010121:Oxytocin; D012964:Sodium; D000242:Cyclic AMP
Arrestin; G Protein-coupled Receptors (GPCR); Kidney Metabolism; Membrane Trafficking; Signaling; V2R