Researchers at Tulane University, along with a team of colleagues from eight other universities, have discovered a new nerve cell signaling mechanism that could transform our understanding of pain and lead to safer and more effective treatments. The study, co-led by Matthew Dalva, director of the Tulane Brain Institute and professor of cellular and molecular biology at the University of Texas at Dallas’s School of Science and Engineering, reveals that neurons can release an enzyme outside the cell that activates pain signaling after an injury. The work, published in Science, offers new insights into how brain cells strengthen their connections during learning and memory.
The researchers discovered that nerve cells communicate outside the cell with the enzyme vertebrate lone kinase (VLK), which can alter proteins in the space between neurons, influencing how these cells send signals. This is one of the first demonstrations that phosphorylation can control how cells interact in the extracellular space. Not that the process of phosphorylation outside cells was unknown, but it had never been explored in depth in intercellular communication processes because almost all known phosphorylation processes occur inside cells to transduce signals activated by hormones, growth factors or cytokines.
The team discovered that active neurons release VLK, which in turn enhances the function of a receptor involved in pain, learning, and memory. This is the NMDAR receptor for glutamate, which interacts with the ephrin adhesion molecule EphB2 to trigger pain induced by external injury. When the scientists removed VLK from pain-sensing neurons in mice, the animals did not experience the usual pain after surgery but continued to move and sense normally. Adding additional VLK had the opposite effect, increasing pain responses. The findings suggest a safer way to influence pain pathways by targeting enzymes like VLK rather than directly blocking NMDA receptors.
The discovery also provides one of the first examples of how to control interactions between cell surface proteins outside the cell, which could simplify drug development and reduce off-target effects, as the drug would not penetrate the cell. A direct application of this discovery is the control of neuropathic pain induced by spinal cord injuries, which affects the quality of life of trauma patients and forces them to use multiple medications to manage it. The next steps are to determine whether this mechanism is specific to a few proteins or part of a broader, underappreciated aspect of biology.
If so, it could reshape therapeutic approaches for neurological and other diseases, such as diabetic neuropathy, which affects at least half of diabetic patients with decades-long disease. Specific inhibitors of this protein kinase are unknown because, despite being a tyrosine kinase (hundreds of inhibitors exist for intracellular tyrosine kinases), none are yet known for VLK, which is an extracellular tyrosine kinase. This new class of drugs could, however, revolutionize some aspects of chronic pain therapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Gourley SL, Srikanth KD et al. Cells. 2021 Dec 7; 10(12):3442.
Srikanth KD et al. Science. 2025 Nov 20; 390(6775):eadp1007.
David ET, Yousuf MS et al. Pharmacol Res. 2024; 206:107284.
