Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation

FEBS Letters

Habib, Aı̈da²  Pawlowski, Marc²  Jandrot-Perrus, Martine¹  Roger, Séverine²  Rosa, Jean-Philippe²  Bryckaert, Marijke² 

[1] E348 INSERM, Faculté Xavier Bichat, Paris, France;U348 INSERM, IFR 6 Circulation Lariboisière, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris Cedex 10, France

关键词: Platelet;    Aggregation;    Extracellular signal-regulated kinase;    Collagen;    P2Y12 receptor;    MAPK;    mitogen-activated protein kinase;    ERK;    extracellular signal-regulated kinase;   

DOI  :  10.1016/S0014-5793(03)01430-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The stimulation of platelets by low doses of collagen induces extracellular signal-regulated kinase 2 (ERK2) activation. In this report, we demonstrate that collagen-induced ERK2 activation depends on thromboxane A₂ (TXA₂) formation and ADP release. The collagen-induced ERK2 activation was inhibited by indomethacin (88%) and by AR-C69931MX (70%), a specific antagonist of P2Y12, a Gi-coupled ADP receptor. AR-C69931MX (10 μM) inhibition was overcome by epinephrine (1 μM), an agonist of the Gi-coupled α_2A-adrenergic receptor, suggesting that the Gi-coupled receptor was necessary for ERK2 activation by collagen. By contrast, MRS 2179 (10 μM), a specific antagonist of P2Y1, a Gq-coupled ADP receptor, did not affect collagen-induced ERK2 activation. Little or no ERK2 activation was observed with ADP alone (10 μM). By contrast, U46619 (10 μM), a stable analog of TXA₂, induced ERK2 activation in an ADP-dependent manner, via the P2Y12 receptor. These results suggest that the Gi-dependent signaling pathway, stimulated by ADP or epinephrine, was not the only pathway required for ERK2 activation by collagen. Costimulation of the specific G_12/13-coupled TXA₂ receptor with a low dose of U46619 (10 nM) and of Gi- and Gq-coupled ADP receptor (10 μM) induced very low levels of ERK2 activation, similar to those observed with ADP alone, suggesting that G_12/13 is not involved or not sufficient to induce the additional pathway necessary for ERK2 activation. The Gq-coupled TXA₂ receptor was required for ERK2 activation by U46619 (10 μM) and low doses of collagen, clearly showing that a coordinated pathway through both Gq from TXA₂ and Gi from ADP was necessary for ERK2 activation. Finally, we demonstrate that ERK2 activation is involved in collagen-induced aggregation and secretion.

【 授权许可】

Unknown