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Impaired thromboxane receptor dimerization reduces signaling efficiency: A potential mechanism for reduced platelet function in vivo

Research output: Contribution to journalArticle

  • Valérie Capra
  • Maria Rosa Accomazzo
  • G. Enrico Rovati
  • Valérie Capra
  • Mario Mauri
  • Francesca Guzzi
  • Marco Parenti
  • Marta Busnelli
  • Pascale Gaussem
  • Shaista P. Nisar
  • Stuart J. Mundell
Original languageEnglish
Pages (from-to)43-56
Number of pages14
JournalBiochemical Pharmacology
Volume124
Early online date11 Nov 2016
DOIs
DateAccepted/In press - 10 Nov 2016
DateE-pub ahead of print - 11 Nov 2016
DatePublished (current) - 15 Jan 2017

Abstract

Thromboxane A2 is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein-coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TPα and TPβ homo-/hetero-dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation. Here, biochemical and pharmacological characterization of this dimer deficient mutant (DDM) in living cells indicates a significant impairment in its response to agonists. Interestingly, two single loss-of-function TPα variants, namely W29C and N42S recently identified in two heterozygous patients affected by bleeding disorders, match some of the residues mutated in our DDM. These two naturally occurring variants display a reduced potency to TP agonists and are characterized by impaired dimer formation in transfected HEK-293T cells. These findings provide proofs that lack of homo-dimer formation is a crucial process for reduced TPα function in vivo, and might represent one molecular mechanism through which platelet TPα receptor dysfunction affects the patient(s) carrying these mutations.

    Research areas

  • G protein coupled receptors, Thromboxane A2, Signal transduction, Receptor dimer, Platelets, Eicosanoids

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0006295216303975?via%3Dihub#f0010. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 668 KB, PDF document

    Licence: CC BY-NC-ND

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