The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain
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/<i>Pkdcc</i>), 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. <i>Pkdcc</i> is an essential gene in the nervous system, and VLK is enriched at synapses and released from neurons in an activity- and soluble <i>N</i>-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.
Authors
- Matthew B. Dalva (ORCID: https://orcid.org/0000-0002-7737-8787)
- Rachel Hodge (ORCID: https://orcid.org/0000-0003-0860-168X)
- Shayne Hassler
- Hajira Elahi (ORCID: https://orcid.org/0000-0001-7080-7262)
- Moeno Kume (ORCID: https://orcid.org/0000-0002-9534-9306)
- Lucy He
- Ishwarya Sankaranarayanan (ORCID: https://orcid.org/0000-0002-6765-0281)
- Patrick M. Dougherty (ORCID: https://orcid.org/0000-0002-2177-2734)
- Stephanie Shiers (ORCID: https://orcid.org/0000-0002-9646-1850)
- Jessica Loucks (ORCID: https://orcid.org/0009-0004-3664-4286)
- Theodore J. Price (ORCID: https://orcid.org/0000-0002-6971-6221)
- Praveen Chander (ORCID: https://orcid.org/0000-0002-7682-3404)
- Zachary T. Campbell (ORCID: https://orcid.org/0000-0002-3768-6996)
- Raehum Paik (ORCID: https://orcid.org/0009-0002-4030-2073)
- Halley R. Washburn (ORCID: https://orcid.org/0000-0002-4774-1987)
- Thomas A. Neubert (ORCID: https://orcid.org/0000-0001-7049-2088)
- Rohita Arjarapu
- Juliet M. Mwirigi (ORCID: https://orcid.org/0000-0002-5220-8239)
- Hediye Erdjument‐Bromage (ORCID: https://orcid.org/0000-0003-0224-3594)
- Khadijah Mazhar (ORCID: https://orcid.org/0000-0002-2469-7469)
- Kolluru D. Srikanth (ORCID: https://orcid.org/0000-0003-4369-667X)
Institutions
- Tulane University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Wisconsin–Madison (US)
- Thomas Jefferson University (US)
- The University of Texas at Dallas (US)
- The University of Texas at San Antonio Health Science Center (US)
- Neurosciences Institute (US)
- Princeton University (US)
- University of Houston (US)
Publication Details
- Journal
- Science
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1126/science.adp1007
- Citations
- 3
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.73