title: G13 is an essential mediator of platelet activation in hemostasis and thrombosis.
abstract: Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.
authors.affiliation: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Moers
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Valerie
authors.initials: V
authors.lastname: Schulte
authors.forename: Barsom
authors.initials: B
authors.lastname: Aktas
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gratacap
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D006487:Hemostasis / Q000502:physiology*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013927:Thrombosis / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D044365:GTP-Binding Protein alpha Subunits, G12-G13