The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain, 2025, Srikanth et al

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Tulane University: "Tulane scientists uncover new pain-signaling switch"

'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,” Dalva 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.”'

Paper

 

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The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain, 2025, Srikanth et al

The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain

Spoiler: Authors

Srikanth, Kolluru D.; Elahi, Hajira; Chander, Praveen; Washburn, Halley R.; Hassler, Shayne; Mwirigi, Juliet M.; Kume, Moeno; Loucks, Jessica; Arjarapu, Rohita; Hodge, Rachel; He, Lucy; Mazhar, Khadijah; Shiers, Stephanie I.; Sankaranarayanan, Ishwarya; Erdjument-Bromage, Hediye; Neubert, Thomas A.; Dougherty, Patrick M.; Campbell, Zachary T.; Paik, Raehum; Price, Theodore J.; Dalva, Matthew B.

Abstract
Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families but the functional role of these kinases is underexplored.

We find that the presynaptic release of the tyrosine-directed ectokinase, vertebrate lonesome kinase (VLK/ Pkdcc ), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses for phosphorylation of the ectodomain of EphB2 and mediation of injury-induced pain.

Pkdcc is an essential gene in the nervous system, and VLK is enriched at synapses and released from neurons in an activity- and soluble N -ethylmaleimide-sensitive factor activating protein receptor (SNARE)–dependent manner to drive extracellular interactions.

Our results show that presynaptic sensory neuron–specific VLK knockout attenuates postsurgical pain in mice without changing sensorimotor performance, suggesting that VLK critically regulates synaptic protein-protein interactions and acute pain in response to injury.

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