3D-illustration of a protein in purple and grey.
Illustration Credit: Courtesy of Karolinska institutet
Scientific Frontline: Extended "At a Glance" Summary: Protein p11 and GPCR Signaling
The Core Concept: The small protein p11 functions as a crucial modulator that interacts with numerous G protein-coupled receptors (GPCRs), amplifying cellular signaling across various physiological networks.
Key Distinction/Mechanism: Rather than acting as a standard receptor trigger, p11 binds preferentially to GPCRs when they are already activated, effectively functioning as an internal signaling amplifier that strengthens cellular responses to stimuli.
Major Frameworks/Components:
- G protein-coupled receptors (GPCRs): The largest receptor family in mammals, which receives signals that dictate mood, immune responses, and pain perception.
- Signal transduction networks: The cellular communication pathways that modern pharmaceuticals aim to tune on or off.
- PAR2 pathways: A specific receptor pathway where p11 amplifies signaling linked to inflammation and pain.
Branch of Science: Cellular Biology, Pharmacology, Clinical Neuroscience, and Receptor Biology.
Future Application: The development of highly precise, next-generation therapies capable of fine-tuning cellular communication to treat chronic pain, inflammatory disorders, and depression.
Why It Matters: Because approximately one-third of all modern, approved medicines target GPCRs, identifying p11 as a universal signaling regulator provides a critical new foundation for advancing receptor biology and optimizing drug design.
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, researcher at the Department of Clinical Neuroscience, KI, 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.
Published in journal: Science Advances
Title: Systematic identification of p11 as a signaling modulator across the GPCRome
Authors: Marcus Saarinen, Ilana B. Kotliar, Inga Höffkes, Niclas Branzell, Carl-Fredrik Bowin, Leo Dahl, Elisa da Silva, Vassilis Glaros, Alonso Abney, Annika Bendes, Taras Kreslavsky, Jochen M. Schwenk, Thomas P. Sakmar, and Per Svenningsson
Source/Credit: Karolinska institutet | Anne Hammarskjöld
Edited by: Scientific Frontline
Reference Number: cbio100126_01