Science1 publisher2 min readPublished
Karolinska screen ties the depression-linked protein p11 to about two dozen more drug-target receptors
Karolinska researchers screened 211 human G protein-coupled receptors and found about two dozen new partners for p11, a protein linked to depression. That makes it a candidate control point for receptors behind a third of approved drugs, though any use in pain or depression remains untested.
The Scientist · Science desk
What happened
- In cell experiments, p11 strengthened signaling through PAR2, a receptor known for its roles in inflammation and pain.
- Mice lacking p11 showed a weaker inflammatory response than normal mice when PAR2 signaling was switched on.
- The study, led by Marcus Saarinen of Karolinska's Department of Clinical Neuroscience, is published in Science Advances.
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Why it matters
- capability The roughly two dozen newly identified receptors give other labs a defined set of p11 pairings to test for functional amplification beyond PAR2.
- constraint Because p11 works with many receptors, a drug that changed p11 levels would likely act on all of them at once, so the authors point toward targeting its contact with specific receptors.
- constraint With animal data limited to PAR2-driven inflammation in mice, any case for p11 as a target in pain or depression has to be built from cell work and earlier studies.
About one in nine receptors on the panel came back as a previously unknown p11 partner [1]. Only one of them, PAR2, was then studied in detail. It was chosen for its known role in inflammation and pain [10].
The list matters because of where p11 came from. Earlier studies tied it to depression and to antidepressant responses, while its wider role in cell signaling stayed unclear [5]. Around a third of approved medicines act through G protein-coupled receptors [4], so a protein that works with many of them is relevant to a large share of existing drugs.
The team combined cell-based assays, cells genetically modified to lack p11, RNA sequencing and experiments in mice [7]. The cells without p11 are the control the amplifier claim needs. If p11 strengthens signaling, removing it should weaken the response, and comparing the two kinds of cell tests exactly that.
The amplifier idea also rests on when p11 binds. It attached preferentially to receptors that were activated [9]. If that pattern holds, its effect would fall on receptors already being stimulated, and the researchers read it as a sign that p11 strengthens cellular responses [9]. For PAR2, the cell data fit: p11 enhanced the receptor's signaling and increased the strength of the responses it triggered [11]. In mice lacking p11, activating PAR2 produced a weaker inflammatory response than in normal mice [12]. The press summary does not say how much weaker.
Marcus Saarinen of Karolinska's Department of Clinical Neuroscience, the lead author, said: "Our study identifies a key protein modulating signal transduction across G protein-coupled receptors, the largest receptor family in mammals." [3]
A protein that works with about two dozen newly identified receptors [8] invites the idea of a single control point for drug signaling. I'd expect a drug that changed p11 itself to act on every receptor it amplifies at once, including receptors a given treatment was never aimed at. The authors' long-term suggestion is narrower: therapies that act on the interaction between p11 and specific receptors, in conditions such as chronic pain and inflammatory disorders [13].
In living animals, the reported test covers one receptor and one outcome, inflammation [12]. Pain was part of the reason PAR2 was picked [10]. The link between p11 and depression comes from earlier studies [5].
What to watch
- Whether the full Science Advances paper reports how much weaker inflammation was in p11-deficient mice, and how the response was measured.
- Whether p11 amplifies signaling at the other newly identified receptors, beyond simply binding them.
- Any mouse test of pain behavior or antidepressant response that depends on p11 working with one specific receptor.