Homologous desensitization of signalling by the beta isoform of the human thromboxane A2 receptor

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Title: Homologous desensitization of signalling by the beta isoform of the human thromboxane A2 receptor
Authors: Kelley-Hickie, Leanne P.Kinsella, B. Therese
Permanent link: http://hdl.handle.net/10197/3146
Date: Sep-2006
Online since: 2011-09-02T13:23:42Z
Abstract: Thromboxane (TX) A2 is a potent stimulator of platelet activation/aggregation and smooth muscle contraction and contributes to a variety of pathologies within the vasculature. In this study, we investigated the mechanism whereby the cellular responses to TXA2 mediated through the TPbeta isoform of the human TXA2 receptor (TP) are dynamically regulated by examining the mechanism of agonist-induced desensitization of intracellular signalling and second messenger generation by TPbeta. It was established that TPbeta is subject to profound agonist-induced homologous desensitization of signalling (intracellular calcium mobilization and inositol 1,3,5 trisphosphate generation) in response to stimulation with the TXA2 mimetic U46619 and this occurs through two key mechanisms: TPbeta undergoes partial agonist-induced desensitization that occurs through a GF 109203X-sensitive, protein kinase (PK)C mechanism whereby Ser145 within intracellular domain (IC)2 has been identified as the key phospho-target. In addition, TPbeta also undergoes more profound and sustained agonist-induced desensitization involving G protein-coupled receptor kinase (GRK)2/3-phosphorylation of both Ser239 and Ser357 within its IC3 and carboxyl-terminal C-tail domains, respectively. Inhibition of phosphorylation of either Ser239 or Ser357, through site directed mutagenesis, impaired desensitization while mutation of both Ser239 and Ser357 almost completely abolished desensitization of signalling, GRK phosphorylation and beta-arrestin association, thereby blocking TPbeta internalization. These data suggest a model whereby agonist-induced PKC phosphorylation of Ser145 partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser239 and Ser357 within its IC3 and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.
Funding Details: Health Research Board
Funding Details: Wellcome Trust
Type of material: Journal Article
Publisher: Elsevier
Journal: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Volume: 1761
Issue: 9
Start page: 1114
End page: 1131
Copyright (published version): 2006 Elsevier B.V.
Keywords: Thromboxane receptorDesensitizationPhosphorylationPhospholipase CG protein coupled receptorG protein coupled receptor kinaseArrestin
Subject LCSH: Thromboxanes
Phosphorylation
Phospholipase C
G proteins
DOI: 10.1016/j.bbalip.2006.07.012
Other versions: http://dx.doi.org/10.1016/j.bbalip.2006.07.012
Language: en
Status of Item: Peer reviewed
ISSN: 1388-1981
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by-nc-sa/1.0/
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection

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