Small protein helps amplify cell signals from receptors targeted by many medicines

A small protein called p11 may play a more significant role in cellular signaling than previously understood. Researchers from Karolinska Institutet have discovered that p11 interacts with numerous receptors targeted by commonly used medications, suggesting new avenues for treating conditions like pain, inflammation, and depression.

Published in the journal Science Advances, the study reveals p11 as a key protein that modulates signal transduction across G protein-coupled receptors (GPCRs), the largest receptor family in mammals. GPCRs are central targets in modern drug development, with approximately one-third of approved medicines acting through these receptors.

Previous research has linked p11 to depression and antidepressant effects, but its broader role in cell signaling remained unclear. By examining interactions between p11 and 211 human GPCRs, the researchers identified around two dozen previously unknown interactions. They found that p11 prefers to bind to receptors when they are activated, likely acting as a signaling amplifier to strengthen cellular responses.

One specific receptor, PAR2, known for its role in inflammation and pain, exhibited enhanced signaling and stronger cellular responses when p11 was present. Mice lacking p11 displayed a weaker inflammatory response when PAR2 signaling was activated, indicating p11's contribution to amplifying inflammatory signaling pathways. These findings suggest that p11 is a previously unrecognized regulator of a wide range of GPCRs, with potential implications for future drug development.

By fine-tuning the interaction between p11 and specific receptors, therapies could be developed to modulate signaling pathways involved in various diseases, including chronic pain, inflammatory disorders, and other conditions linked to GPCR function.