# Mechanism for feedback regulation of G protein-coupled receptor signaling in platelets

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Achieving hemostasis following vascular injury while avoiding excessive platelet accumulation
requires that signaling is closely regulated in resting and activated platelets. Most platelet
agonists work through G protein coupled receptors (GPCRs). Our goals are to dissect how
GPCRs and G proteins can be regulated by GPCR kinases (GRKs) during platelet activation
and thrombus formation, and to understand how dysfunctional regulation of GRKs may lead to
thrombotic events and cardiovascular disease. In the past two decades, GRKs have been
shown to play an important role in the heart by regulating GPCR signaling. Changes in GRK
expression have been linked to many cardiovascular pathologies. However, the contribution of
GRKs to platelet activation and the role of GRKs in hemostasis and thrombosis are unknown.
Our hypothesis is that GRKs are critical negative regulators of platelet activation and thrombus
formation. We base our hypothesis on preliminary studies from our lab showing that 1) The
RGS-resistant G188S mutation in Gq prevents RGS protein binding but surprisingly increases
GRK2 binding; 2) GRK2 binding is specific to Gq, but not to Gi2; 3) In contrast to enhanced Gi2
signaling in RGS-resistant Gi2(G184S) mutant platelets, there is decreased platelet activation in
Gq(G188S) platelets; 4) Deletion of GRK2, GRK5 or GRK6 in platelets causes an increase in
platelet activation. The hypothesis will be tested in three specific aims. In Aim 1, we will examine
the role of G protein and GRKs interactions in regulating platelet function. In Aim 2, we will
determine the role of GRK2 in hemostasis and thrombosis. we will be the first to characterize
the functions of GRK2 in hemostasis and thrombosis and identify the non-canonical roles of
GRK2 in platelets. In Aim 3, we will determine the role of GRK5/6 in hemostasis and thrombosis
and explore the effect of two human GRK5 genetic variants on platelet function using
CRISPR-Cas9 edited iPSCs (induced pluripotent stem cells). These proposed studies are
innovative because we combine recent genome-wide association studies (GWAS) identified
human GRK5 genetic variants, 4 newly generated mouse mutant lines and CRISPR-cas9 edited
iPSC cells to study the uncharacterized role of GRKs in platelets. This study is significant
because a critical gap in knowledge exists between unexplored functions of GRK family in
platelets and their well-studied roles in the cardiovascular system. Through these studies, we
will advance our understanding of the role of GRKs in cardiovascular health and disease, and
the gained information may lead to new therapeutic options for the treatment of thrombotic and
cardiovascular disorders.

## Key facts

- **NIH application ID:** 9990885
- **Project number:** 5R01HL144574-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Peisong Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990885

## Citation

> US National Institutes of Health, RePORTER application 9990885, Mechanism for feedback regulation of G protein-coupled receptor signaling in platelets (5R01HL144574-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990885. Licensed CC0.

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