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Brass 1 7 Show more Add to Mendeley Share Cite Get rights and content Abstract G proteincoupled receptors are critical mediators of platelet activation whose signaling can be modulated by members of the regulator of G protein signaling (RGS) family.The 2 most abundant RGS proteins in human and mouse platelets are RGS10 and RGS18.While each has been studied individually, critical questions remain about the overall impact of this mode of regulation in platelets.Here, we report that mice missing both proteins show reduced platelet survival and a 40 decrease in platelet count that can be partially reversed with aspirin and a P2Y 12 antagonist.
Their platelets have increased basal (TREM)-like transcript-1 expression, a leftward shift in the doseresponse for a thrombin receptoractivating peptide, an increased maximum response to adenosine 5-diphosphate and TxA 2, and a greatly exaggerated response to penetrating injuries in vivo. Neither of the individual knockouts displays this constellation of findings. RGS10 platelets have an enhanced response to agonists in vitro, but platelet count and survival are normal. RGS18 mice have a 15 reduction in platelet count that is not affected by antiplatelet agents, nearly normal responses to platelet agonists, and normal platelet survival. Megakaryocyte number and ploidy are normal in all 3 mouse lines, but platelet recovery from severe acute thrombocytopenia is slower in RGS18 and RGS10 18 mice. Collectively, these results show that RGS10 and RGS18 have complementary roles in platelets. Removing both at the same time discloses the extent to which this regulatory mechanism normally controls platelet reactivity in vivo, modulates the hemostatic response to injury, promotes platelet production, and prolongs platelet survival. The data sets, protocols, and mice in this study will be made available to other investigators per the policies of the National Institutes of Health, the University of Pennsylvania, and this journal. The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked advertisement in accordance with 18 USC section 1734. Prepublished online as Blood First Edition paper, June 15, 2020 Much is known about how platelet activation is triggered, but less is understood about its negative regulation and how this is molecularly controlled. Using knockout mice, DeHelian et al reveal that 2 members of the regulator of G protein signaling (RGS) family, RGS10 and RGS18, play important roles in dampening agonist-induced platelet activation and thrombus growth at sites of vascular injury. Copyright 2020 American Society of Hematology All rights reserved. Citing articles Article Metrics View article metrics About ScienceDirect Remote access Shopping cart Advertise Contact and support Terms and conditions Privacy policy We use cookies to help provide and enhance our service and tailor content and ads. Copyright 2021 Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V.
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