ArticleBlood advances2020
GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- G protein-coupled receptor-mediated platelet thrombus formation.Current opinion in hematology · 2026Review
- Red blood cell membrane proteome as a reporter of disease severity, transfusion impact and genetic background in transfusion-dependent β-thalassaemia.British journal of haematology · 2026Article
- Understanding how a highly prevalent GRK5 polymorphism affects platelets and enhances thrombotic risk.Blood · 2026Article
- Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity.Scientific reports · 2025Article
- Phosphatidylserine-blocking nanoparticles inhibit thrombosis without increased bleeding in mice.Journal of thrombosis and haemostasis : JTH · 2025Article
- Roles of G proteins and their GTPase-activating proteins in platelets.Bioscience reports · 2024Review
- Plasma growth factors maintain constitutive translation in platelets to regulate reactivity and thrombotic potential.Blood advances · 2024Article
- A regulatory node involving GαJournal of thrombosis and haemostasis : JTH · 2023Article
- Species Differences in Platelet Protease-Activated Receptors.International journal of molecular sciences · 2023Review
- GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.Blood advances · 2022Article
- G protein-coupled receptor kinase 5 regulates thrombin signaling in platelets via PAR-1.Blood advances · 2022Article
- Platelet proteome dynamics in hibernating 13-lined ground squirrels.Physiological genomics · 2021Article
- The GRKs Reactome: Role in Cell Biology and Pathology.International journal of molecular sciences · 2021Review
- The Roles of GRKs in Hemostasis and Thrombosis.International journal of molecular sciences · 2020Review
- Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization.International journal of molecular sciences · 2020Article
- Mouse laser injury models: variations on a theme.Platelets · 2020Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
G protein-coupled receptors (GPCRs) mediate the majority of platelet activation in response to agonists. However, questions remain regarding the mechanisms that provide negative feedback toward activated GPCRs to limit platelet activation and thrombus formation. Here we provide the first evidence that GPCR kinase 6 (GRK6) serves this role in platelets, using GRK6-/- mice generated by CRISPR-Cas9 genome editing to examine the consequences of GRK6 knockout on GPCR-dependent signaling. Hemostatic thrombi formed in GRK6-/- mice are larger than in wild-type (WT) controls during the early stages of thrombus formation, with a rapid increase in platelet accumulation at the site of injury. GRK6-/- platelets have increased platelet activation, but in an agonist-selective manner. Responses to PAR4 agonist or adenosine 5'-diphosphate stimulation in GRK6-/- platelets are increased compared with WT littermates, whereas the response to thromboxane A2 (TxA2) is normal. Underlying these changes in GRK6-/- platelets is an increase in Ca2+ mobilization, Akt activation, and granule secretion. Furthermore, deletion of GRK6 in human MEG-01 cells causes an increase in Ca2+ response and PAR1 surface expression in response to thrombin. Finally, we show that human platelet activation in response to thrombin causes an increase in binding of GRK6 to PAR1, as well as an increase in the phosphorylation of PAR1. Deletion of GRK6 in MEG-01 cells causes a decrease in PAR1 phosphorylation. Taken together, these data show that GRK6 regulates the hemostatic response to injury through PAR- and P2Y12-mediated effects, helping to limit the rate of platelet activation during thrombus growth and prevent inappropriate platelet activation.
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