A new on-switch for pain signaling pathway
Researchers have discovered a new nerve cell signaling mechanism that could transform our understanding of pain and lead to safer, more effective treatments.
The study reveals that neurons can release an enzyme outside the cell that switches on pain signaling after injury. The work, published in Science, offers new insight into how brain cells strengthen their connections during learning and memory.
“This finding changes our fundamental understanding of how neurons communicate,” the author said. “We’ve discovered that an enzyme released by neurons can modify proteins on the outside of other cells to turn on pain signaling — without affecting normal movement or sensation.”
Researchers found that nerve cells communicate outside the cell with the enzyme vertebrate lonesome kinase (VLK), which can alter proteins in the space between neurons, affecting how those cells send signals.
“This is one of the first demonstrations that phosphorylation can control how cells interact in the extracellular space,” the author said. “It opens up an entirely new way of thinking about how to influence cell behavior and potentially a simpler way to design drugs that act from the outside rather than having to penetrate the cell.”
The team discovered that active neurons release VLK, which then boosts function of a receptor involved in pain, learning and memory. When the scientists removed VLK from pain-sensing neurons in mice, the animals didn’t feel the usual pain after surgery but still moved and sensed normally. Adding extra VLK had the opposite effect, increasing pain responses.
The authors show that VLK phosphorylated EphB2 at Y504 in an ATP-dependent manner, and this effect was blocked by extracellular phosphatase and absent with VLK-kinase–dead mutants. Recombinant VLK (rVLK) induced EphB2–NMDAR complex formation in cultured neurons and spinal tissue, whereas Pkdcc knockout abolished the interaction.
VLK localized to synaptic vesicles and was released in a SNARE-dependent manner following ephrin-B stimulation or elevated neuronal activity, consistent with regulated synaptic release.
“This study gets to the core of how synaptic plasticity works — how connections between neurons evolve,” said a co-corresponding author of the study. “It has very broad implications for neuroscience, especially in understanding how pain and learning share similar molecular mechanisms.”
The author said the findings point to a safer way to influence pain pathways by targeting enzymes like VLK rather than directly blocking NMDA receptors, which help regulate communication between nerve cells but can cause serious side effects when disrupted.
The finding also provides one of the first examples of how to control interactions between cell-surface proteins outside the cell, which may simplify drug development and reduce off-target effects, since the drug would not enter the cell, the author said.
Next steps are to see whether this is a mechanism specific to just a few proteins or part of a broader and underappreciated aspect of biology, and if so, it could reshape treatment approaches for neurological and other diseases, the author said.
