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Updated: May 8, 2026

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Regulator of G Protein Signaling 6 Negatively Regulates Platelet Activation and Arterial Thrombosis in Mice

Renat Roytenberg1, Boyd R Rorabaugh2, Hong Yue1

  • 1Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV.

Biorxiv : the Preprint Server for Biology
|May 7, 2026
PubMed
Abstract

Insights

Regulator of G protein Signaling 6 (RGS6) negatively regulates platelet activation and arterial thrombosis by inhibiting P2Y12/Gi signaling. Loss of RGS6 accelerates thrombosis, highlighting its role as an endogenous brake on platelet function.

Area of Science:

  • Cardiovascular Biology
  • Thrombosis Research
  • G Protein-Coupled Receptor Signaling

Background:

  • Platelet activation via GPCRs is crucial for arterial thrombosis.
  • P2Y12 receptor is a key mediator of ADP-dependent platelet activation.
  • The role of RGS6 in platelet function and thrombosis is not well understood.

Purpose of the Study:

  • To investigate the role of RGS6 in platelet activation and arterial thrombosis.
  • To define the impact of RGS6 on P2Y12/Gi signaling pathways.

Main Methods:

  • Assessed arterial thrombosis using a FeCl3-induced carotid artery injury model in wild-type and RGS6 knockout mice.
  • Measured ex vivo platelet aggregation and analyzed signaling pathways via Western blot.
  • Evaluated P2Y12/Gi signaling using a cAMP-responsive luciferase reporter assay in HEK293 cells.

Main Results:

  • RGS6 knockout mice showed accelerated thrombosis and enhanced ADP-induced platelet aggregation.
  • RGS6 deficiency altered signaling kinetics, including delayed Akt and reduced PKA/VASP phosphorylation.
  • RGS6 attenuated P2Y12/Gi-mediated cAMP suppression, acting as a negative regulator.

Conclusions:

  • RGS6 is a negative regulator of platelet P2Y12/Gi signaling and thrombus formation.
  • Loss of RGS6 enhances ADP-dependent platelet activation and accelerates arterial thrombosis.
  • RGS6 functions as an endogenous brake on platelet activation and thrombosis.
Keywords:
G protein-coupled receptorsGi alpha subunitPlateletRegulator of G protein signaling 6Thrombosis

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