FcgammaRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation.
FcgammaRIIA, the only Fcgamma receptor present in platelets, is involved in heparin-associated thrombocytopenia (HIT). Recently, adenosine diphosphate (ADP) has been shown to play a major role in platelet activation and aggregation induced by FcgammaRIIA cross-linking or by sera from HIT patients. Herein, we investigated the mechanism of action of ADP as a cofactor in FcgammaRIIA-dependent platelet activation, which is classically known to involve tyrosine kinases. We first got pharmacologic evidence that the ADP receptor coupled to Gi was required for HIT sera or FcgammaRIIA clustering-induced platelet secretion and aggregation. Interestingly, the signaling from this ADP receptor could be replaced by triggering another Gi-coupled receptor, the alpha(2A)-adrenergic receptor. ADP scavengers did not significantly affect the tyrosine phosphorylation cascade initiated by FcgammaRIIA cross-linking. Conversely, the Gi-dependent signaling pathway, initiated either by ADP or epinephrine, was required for FcgammaRIIA-mediated phospholipase C activation and calcium mobilization. Indeed, concomitant signaling from Gi and FcgammaRIIA itself was necessary for an efficient synthesis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase Cgamma2 activation. Altogether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induced by FcgammaRIIA.
Gratacap
M P
MP
Institut Fédératif de Recherche en Immunologie Cellulaire et Moléculaire, Université Paul Sabatier and Centre Hospitalo, 31059 Toulouse Cedex, France.
Hérault
J P
JP
Viala
C
C
Ragab
A
A
Savi
P
P
Herbert
J M
JM
Chap
H
H
Plantavid
M
M
Payrastre
B
B
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000925:Anticoagulants / Q000009:adverse effects; D015703:Antigens, CD / Q000494:pharmacology / Q000502:physiology*; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000494:pharmacology / Q000502:physiology; D006493:Heparin / Q000009:adverse effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013921:Thrombocytopenia / Q000139:chemically induced / Q000473:pathology; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000925:Anticoagulants; D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; D018341:Receptors, Adrenergic, alpha-2; D017452:Receptors, IgG; D018048:Receptors, Purinergic P2; C060974:phosphatidylinositol 3,4,5-triphosphate; D014443:Tyrosine; D000244:Adenosine Diphosphate; D006493:Heparin; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D019204:GTP-Binding Proteins; D004837:Epinephrine