# P2X3 is a Female-Dominant Amplifier of Mast Cell Function

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $369,992

## Abstract

Project Summary
The rising incidence of allergic disease is a public health challenge needing novel interventions. While mast
cell activation by IgE has a known role in disease pathology, fundamental aspects of mast cell biology remain
unclear. There is a particular need to understand sex-specific effects. Mast cells from female mice have
stronger IgE-induced responses, an observation complementing the greater incidence and acuity of allergic
asthma among women. In an effort to repurpose drugs, we found that fluoxetine (Prozac) potently suppresses
mast cell activation by IgE. These data were consistent in vitro, in vivo, and with human mast cells. However,
fluoxetine effects were strikingly female-restricted. Our results indicate fluoxetine has an off-target effect on
P2X3, an ATP-activated cationic channel most often associated with pain signaling. We find that mast cells
rapidly release ATP in response to IgE signaling, suggesting P2X3 is triggered in an autocrine loop. P2X3 was
readily detectable on female but not male mast cells and may explain why female mast cells have stronger IgE
responses. Like fluoxetine, P2X3-selective inhibitors greatly suppressed mast cell responses to IgE or ATP.
Inhibitors of other P2X proteins had no effect. Our study will test the hypothesis that IgE signaling elicits ATP
release that activates P2X3 selectively in females, amplifying allergic inflammation. This pathway could offer
an explanation and a clinical target for sexual dimorphism in allergic disease.
We have three Specific Aims:
Aim 1: We will test the hypothesis that P2X3 enhances mast cell function in females.
Aim 2: We will test the hypothesis that fluoxetine acts by suppressing P2X3 function and expression.
Aim 3: We will test the hypothesis that P2X3 is a fundamental part of allergic airway inflammation that can be
targeted in females.

## Key facts

- **NIH application ID:** 10317599
- **Project number:** 1R01AI164710-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** John J Ryan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,992
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317599

## Citation

> US National Institutes of Health, RePORTER application 10317599, P2X3 is a Female-Dominant Amplifier of Mast Cell Function (1R01AI164710-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317599. Licensed CC0.

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