Faculty Collaboration Database

RGS10 and RGS18 differentially limit platelet activation, promote platelet production, and prolong platelet survival. Blood 2020 Oct 08;136(15):1773-1782

Date

06/17/2020

Pubmed ID

32542378

Pubmed Central ID

PMC7544544

DOI

10.1182/blood.2019003251

Scopus ID

2-s2.0-85091123116 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

G protein-coupled 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 P2Y12 antagonist. Their platelets have increased basal (TREM)-like transcript-1 expression, a leftward shift in the dose/response for a thrombin receptor-activating peptide, an increased maximum response to adenosine 5'-diphosphate and TxA2, 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.

Author List

DeHelian D, Gupta S, Wu J, Thorsheim C, Estevez B, Cooper M, Litts K, Lee-Sundlov MM, Hoffmeister KM, Poncz M, Ma P, Brass LF

Author

Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Cell Survival
Mice
Mice, Knockout
Phosphorylation
Platelet Activating Factor
Platelet Activation
Platelet Aggregation Inhibitors
Platelet Count
RGS Proteins
Thrombopoiesis