A new mechanism of synaptic plasticity has emerged: extracellular phosphorylation by secreted kinases in the synaptic cleft, notably vertebrate lonesome kinase (VLK), which governs EphB2–NMDA receptor interactions and injury-induced pain.

In mouse experiments, removing VLK from pain-sensing neurons reduced postoperative pain without impairing normal motor or sensory functions; conversely, increasing VLK amplified pain responses.

The findings point to potential therapies that locally inhibit VLK to relieve pain, possibly avoiding side effects tied to direct NMDA receptor modulation.

Co-first authors Kolluru Srikanth, Praveen Chander, and Halley Washburn are from The Dalva Lab at Tulane.

Researchers Ted Price and Matthew Dalva led the work, published in Science, detailing how VLK drives the EphB2–NMDA receptor interaction.

The study highlights cross-institution collaboration and notes that extracellular phosphorylation has been observed before, but its role in the nervous system was largely unclear until now.

The work suggests a broader mechanism where extracellular phosphorylation can influence cell interactions, potentially simplifying drug development and reducing off-target effects by avoiding cell entry.

Next steps aim to determine whether this mechanism applies to other proteins and biological processes, which could reshape treatments for neurological and other diseases.

Further exploration will assess the applicability of this mechanism to a wider set of proteins and processes, with potential broad biological relevance.

In vivo experiments show that presynaptic deletion of Pkdcc disrupts EphB2 phosphorylation and blocks EphB2–NMDA receptor interaction in dorsal horn neurons after injury, without altering baseline protein expression.

The Science report, published November 20, 2025, is titled The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain (DOI: 10.1126/science.adp1007).

The research consortium includes UT Dallas, UT Health San Antonio, UT MD Anderson, University of Houston, Princeton, UW–Madison, NYU Grossman School of Medicine, and Thomas Jefferson University, with NIH support from NINDS, NIDA, and NCRR.

Key authors include Hajira Elahi, Ted Price, and Matthew Dalva, with UT Dallas CAPS as a major contributor; the Science publication dates reflect November 2024 and November 2025 milestones across multiple institutions.

Genetic knockout of Pkdcc (VLK) abolishes EphB2–NMDA receptor signaling, while kinase-dead VLK mutants fail to promote the pathway, indicating the kinase activity is essential.