Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase.
p38 MAP kinase in human platelets is activated by platelet agonists including thrombin, thromboxane A2 (TxA2), ADP, and others. However, both upstream mechanisms of p38 MAP kinase activation, and their downstream sequelae, are presently controversial and essentially unclear. Certain studies report sequential activation of cGMP-dependent protein kinase (PKG) and p38/ERK pathways by platelet agonists, leading to integrin activation and secretion, whereas others establish an essential role of Src/ERK-mediated TxA2 generation for fibrinogen receptor activation in human platelets. Here, we show that ADP secreted from platelet-dense granules, and subsequent activation of P2Y12 receptors, as well as TxA2 release are important upstream mediators of p38 MAP kinase activation by thrombin. However, p38 MAP kinase activation did not significantly contribute to calcium mobilization, P-selectin expression, alphaIIbbeta3 integrin activation, and aggregation of human platelets in response to thrombin. Finally, PKG activation did not stimulate, but rather inhibited, p38 MAP kinase in human platelets.
Begonja
Antonija Jurak
AJ
Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany.
Geiger
Jörg
J
Rukoyatkina
Natalia
N
Rauchfuss
Steffen
S
Gambaryan
Stepan
S
Walter
Ulrich
U
D000244:Adenosine Diphosphate / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology*; D013928:Thromboxane A2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D017869:Cyclic GMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D002118:Calcium