Protein found to regulate dozens of important drug targets
A small protein known as p11 may play a much broader role in cellular signaling than previously thought. Researchers at Karolinska institutet have now shown that p11 interacts with numerous receptors targeted by commonly used medicines, opening new possibilities for treating conditions such as pain, inflammation and depression.
"Cells communicate through complicated molecular networks, with most modern drugs acting by tuning these signals on or off. Our study identifies a key protein modulating signal transduction across G protein-coupled receptors, the largest receptor family in mammals. Decoding these signaling networks is essential to advance receptor biology and drive the development of next-generation therapies," says Marcus Saarinen at the Department of Clinical Neuroscience and lead author of the study.
A hidden regulator of cellular communication
Cells communicate with each other through signaling pathways that control everything from mood and pain perception to immune responses. Many of these signals are received by a family of receptors called G protein-coupled receptors (GPCRs), which are among the most important targets in modern drug development. Around one-third of approved medicines act through GPCRs.
Previous studies have linked the protein p11 to depression and antidepressant responses, but its broader role in cell signaling has remained unclear. To investigate this, the researchers examined whether p11 interacts with a large number of GPCRs found in the human body.
More interactions than expected
The team screened 211 human GPCRs and combined several experimental approaches, including cell-based assays, genetically modified cells lacking p11, RNA sequencing and studies in mice.
The researchers identified around two dozen previously unknown GPCRs that interact with p11. They also found that p11 preferentially binds to receptors when they are activated, suggesting that it acts as a signaling amplifier that strengthens cellular responses.
One receptor, PAR2, was studied in greater detail because of its known role in inflammation and pain. Experiments showed that p11 enhanced PAR2 signaling and increased the strength of cellular responses triggered by the receptor.
Potential implications for future therapies
To determine whether the findings were relevant in living organisms, the researchers studied mice that lacked p11. When PAR2 signaling was activated, these animals showed a weaker inflammatory response than normal mice, indicating that p11 contributes to the amplification of inflammatory signaling pathways.
The findings suggest that p11 is a previously unrecognized regulator of a wide range of GPCRs. Because these receptors are involved in many common diseases and are frequent targets of medicines, the discovery could have important implications for future drug development.
In the long term, therapies designed to influence the interaction between p11 and specific receptors may make it possible to fine-tune signaling pathways involved in conditions such as chronic pain, inflammatory disorders and other diseases linked to GPCR function. The study therefore provides both new insight into fundamental cellular communication and a potential starting point for the development of more precise treatments.
See the study for information on funding and any reported conflicts of interest.
Publication
"Systematic identification of p11 as a signaling modulator across the GPCRome" Saarinen M, Kotliar I B, Höffkes I, Bowin C-F, Dahl L, Da Silva E, Glaros V, Abney A, Bendes A, Kreslavsky T, Schwenk J M, Sakmar T P, Svenninsson P. Science Advances, online 30 September 2026, doi: 10.1126/sciadv.aeg6567.