# Molecular mechanisms of TRPA1 regulation

> **NIH NIH R35** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

PROJECT SUMMARY
The wasabi receptor, TRPA1, is a non-selective homotetrameric cation channel expressed in primary
sensory neurons where its activation by noxious chemical irritants contributes to pain perception and
local inflammation. Local inflammatory cues, in turn, sensitize sensory neurons to painful stimuli. Within
the pain and local inflammation regulatory cycle, TRPA1 serves as a positive regulator and its
dysregulation could contribute to the development of chronic pain. Genetic loss of TRPA1 in mice
abrogates pain perception to chemical irritants, mechanical and thermal hypersensitivity produced from
tissue injury, and asthma-induced airway inflammation supporting this model. Gain-of-function TRPA1
mutations cause congenital painful disorders in humans highlighting its direct role in pain perception.
This makes understanding TRPA1 function and dysregulation highly significant. Basic science research
in the Paulsen Laboratory broadly aims to determine molecular mechanisms of TRPA1 regulation and
dysregulation by second messengers, local inflammatory cues, through protein-protein interactions,
and as imparted by novel gain-of-function mutations. High-resolution TRPA1 structures exist in the
open and closed states, which are sampled during normal channel activity. While they represent a
major advance, these structures do not address the fundamental question of how TRPA1 becomes
sensitized to confer channel hyperactivity in disease. Understanding these mechanisms would open
the door to develop new targeted therapeutics. During the next 5 years, we will use complementary
biochemical, biophysical, and structural biology approaches to determine the molecular basis of
channel hyperactivity conferred by a novel gain-of-function TRPA1 mutation. Our preliminary data
suggest this TRPA1 mutant protein co-assembles with wild type TRPA1 subunits to form hyperactive
channels. We want to understand how the structural alterations introduced by this TRPA1 mutant affect
channel function. Additionally, we will determine how TRPA1 is sensitized and/or activated by calcium
and calmodulin. Many local inflammatory cues indirectly activate TRPA1 downstream of G-protein
coupled receptors that promote intracellular calcium release. TRPA1 could bind calcium directly or the
universal calcium sensor, calmodulin could mediate calcium sensing. Our preliminary data support an
interplay of calcium and calmodulin in regulating TRPA1 and we want to understand how calmodulin
binding works in concert with calcium-binding sites to confer TRPA1 calcium-dependent channel
activity. Collectively, this work will enhance our understanding of regulation and dysregulation of TRPA1
at the molecular level and will uncover novel avenues for drug development to target aberrant channels
in chronic pain and inflammatory conditions.

## Key facts

- **NIH application ID:** 10275544
- **Project number:** 1R35GM142825-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Candice Elaine Paulsen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275544

## Citation

> US National Institutes of Health, RePORTER application 10275544, Molecular mechanisms of TRPA1 regulation (1R35GM142825-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10275544. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*