Active Cells, Biochemistry & Physiology Genetics & Molecular Biology

Assembly and disassembly of β-arrestin-centred signalling complexes – how scaffolding proteins regulate PAR2-mediated pain in inflammation

Funder Wellcome Charity-funded
Recipient organisation University of Nottingham
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

Inflammatory pain begins when a protein called PAR2, sitting on the surface of nerve cells, gets activated by enzymes released during tissue damage. This project will watch, in living cells, how a scaffolding protein called β-arrestin assembles a team of signalling molecules around PAR2 to drive that pain signal. Current pain treatments for conditions like inflammatory bowel disease often target PAR2 indirectly, with limited success, because scientists do not fully understand how β-arrestins control the receptor’s activity. Without that knowledge, drug developers are essentially working blind. This research fills that gap by mapping exactly which proteins β-arrestin recruits, and in what order, using advanced microscopy and a new three-component recruitment assay the team is building. If successful, this fundamental science will reveal the molecular choreography of inflammatory pain signalling. That deeper understanding could eventually allow researchers to design drugs that block pain at its source—for example, by disrupting the specific β-arrestin–effector interactions that drive chronic pain in IBD—without interfering with other GPCR functions elsewhere in the body. No immediate clinical application is promised, but similar mechanistic studies of GPCR signalling have previously led to blockbuster pain drugs.

View original technical description
This project investigates the pivotal role of G protein-coupled receptors (GPCRs) in inflammation, with a focus on protease-activated receptor 2 (PAR2), a central mediator of inflammation-induced pain. While key transducers such as G proteins mediate PAR2 signalling, the involvement of β-arrestins (important regulators of GPCR functions) in PAR2 signalling remains underexplored. This gap in understanding poses a barrier to the advancement of therapies targeting PAR2-mediated pain in inflammation. Recent data from our group suggests that β-arrestins act as key scaffolding proteins that attract a variety of signalling and trafficking effectors to active GPCRs by changing their conformational state to enable these interactions. Here, we seek to uncover the mechanisms driving inflammatory pain by characterising β-arrestin-centred signalling complexes, with the potential to reveal new therapeutic targets for pain management. Molecular mechanisms will be investigated, in living cells, using advanced microscopy techniques while developing a novel, subcellularly localised three-component recruitment assay, to investigate the assembly of β-arrestin-centred complexes that regulate PAR2 signalling. Additionally, proximity-based proteomics will be implemented to identify unknown components of these signalling complexes. Understanding these fundamental mechanisms is vital to enable the development of novel, possibly location-specific medicines to tackle persistent pain in IBD and other inflammatory pathologies.

View the original record at the funder ↗

Researchers

Claire Kelly (EPMC Awardee)

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Original classification

PhD Studentship (Basic)

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