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Homologous desensitization of signalling by the beta isoform of the human thromboxane A2 receptor
Date Issued
2006-09
Date Available
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.
Sponsorship
Health Research Board
Other Sponsorship
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.
Subject – LCSH
Thromboxanes
Phosphorylation
Phospholipase C
G proteins
Web versions
Language
English
Status of Item
Peer reviewed
ISSN
1388-1981
This item is made available under a Creative Commons License
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Kelley_&_Kinsella__Hom_Desens_TPb_BBA_2006_incEratum.pdf
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520.51 KB
Format
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