Document Type

Article

Publication Date

8-28-2018

Comments

This research was originally published in Blood Advances. Ma, P., Gupta, S., Sampietro, S., DeHelian, D., Tutwiler, V., Tang, A., Stalker, T.J., and Brass, L. F. RGS10 shapes the hemostatic response to injury through its differential effects on intracellular signaling by platelet agonists. Blood Adv. 2018:2(16):2145-2155. © the American Society of Hematology.

The original published version is available at https://doi.org/10.1182/bloodadvances.2017008508.

Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund

Abstract

Platelets express ≥2 members of the regulators of G protein signaling (RGS) family. Here, we have focused on the most abundant, RGS10, examining its impact on the hemostatic response in vivo and the mechanisms involved. We have previously shown that the hemostatic thrombi formed in response to penetrating injuries consist of a core of fully activated densely packed platelets overlaid by a shell of less-activated platelets responding to adenosine 5'-diphosphate (ADP) and thromboxane A2 (TxA2). Hemostatic thrombi formed in RGS10-/- mice were larger than in controls, with the increase due to expansion of the shell but not the core. Clot retraction was slower, and average packing density was reduced. Deleting RGS10 had agonist-specific effects on signaling. There was a leftward shift in the dose/response curve for the thrombin receptor (PAR4) agonist peptide AYPGKF but no increase in the maximum response. This contrasted with ADP and TxA2, both of which evoked considerably greater maximum responses in RGS10-/- platelets with enhanced Gq- and Gi-mediated signaling. Shape change, which is G13-mediated, was unaffected. Finally, we found that free RGS10 levels in platelets are actively regulated. In resting platelets, RGS10 was bound to 2 scaffold proteins: spinophilin and 14-3-3γ. Platelet activation caused an increase in free RGS10, as did the endothelium-derived platelet antagonist prostacyclin. Collectively, these observations show that RGS10 serves as an actively regulated node on the platelet signaling network, helping to produce smaller and more densely packed hemostatic thrombi with a greater proportion of fully activated platelets.

PubMed ID

30150297

Language

English

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