# Novel Roles of GRK2 and beta-arrestin2  on mast cell-mediated allergy and Inflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $483,656

## Abstract

Summary:
 Mast cell (MC) activation through the aggregation of cell surface IgE receptors (FcεRI) leads to life-
threatening conditions such as anaphylaxis and asthma. Recent exciting development in MC biology has been
the discovery that they express a novel G protein coupled receptor (GPCR) known as MRGPRX2 (mouse
counterpart MrgprB2), which contributes to a growing list of conditions such as pseudoallergy, neurogenic
inflammation, non-histaminergic itch, allergic contact dermatitis and atopic dermatitis. The main objective of
this proposal is to modulate FcεRI and MrgprB2-mediated responses by targeting novel signaling pathways in
MCs.
 Following their activation, most GPCRs undergo desensitization via their phosphorylation by GPCR
kinases (GRKs) and the recruitment of the adapter proteins, β-arrestins (β-arrs). We made four novel
observations, which provide the basis of this proposal. First, we found that unlike most GPCRs, MRGPRX2 is
resistant to GRK2-mediated desensitization but it contributes to IgE-mediated MC degranulation and cytokine
production. Second, β-arr2 inhibits both IgE and MrgprB2-mediated MC degranulation by modifying unknown
components downstream of Ca2+ mobilization. Third, β-arr2 contributes to MC chemotaxis in vitro and allergic
contact dermatitis in vivo. Fourth, the effect of β-arr2 on MC chemotaxis is associated with Ser3
dephosphorylation of the actin depolymerization factor cofilin. While activation of protein kinase Cβ (PKCβ)
promotes MC degranulation, PKCα phosphorylates cofilin at Ser23 and Ser24 to increase actin polymerization,
resulting in cessation of degranulation. Based on these findings, we hypothesize that GRK2 promotes IgE-
mediated responses in MCs via the regulation of Syk/Akt/NF-κB signaling but β-arr2 modulates both FcεRI and
MrgprB2 responses by functioning as a scaffolding protein for phosphorylation and dephosphorylation of cofilin.
In aim 1, we will determine the role of GRK2 on FcεRI-mediated MC degranulation and cytokine generation in
vitro and allergic response in vivo. In aim 2, we will determine the role of β-arr2 on FcεRI and MrgprB2-
resposnes in vitro and inflammatory responses in vivo. Completion of this study may provide better rationale
for the development of novel therapeutics for the MC-mediated disorders.

## Key facts

- **NIH application ID:** 10058511
- **Project number:** 1R01AI143185-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Hydar Ali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,656
- **Award type:** 1
- **Project period:** 2020-05-14 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058511

## Citation

> US National Institutes of Health, RePORTER application 10058511, Novel Roles of GRK2 and beta-arrestin2  on mast cell-mediated allergy and Inflammation (1R01AI143185-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10058511. Licensed CC0.

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