Impaired thromboxane receptor dimerization reduces signaling efficiency: a potential mechanism for reduced platelet function in vivo
Articolo
Data di Pubblicazione:
2017
Citazione:
Impaired thromboxane receptor dimerization reduces signaling efficiency: a potential mechanism for reduced platelet function in vivo / V. Capra, M. Mauri, F. Guzzi, M. Busnelli, M.R. Accomazzo, P. Gaussem, S.P. Nisar, S.J. Mundell, M. Parenti, G.E. Rovati. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 124(2017), pp. 43-56.
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
G protein coupled receptors; Thromboxane A(2); Signal transduction; Receptor dimer; Platelets; Eicosanoids
Elenco autori:
V. Capra, M. Mauri, F. Guzzi, M. Busnelli, M.R. Accomazzo, P. Gaussem, S.P. Nisar, S.J. Mundell, M. Parenti, G.E. Rovati
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