课题组人员发现酪氨酸导向的外激酶，脊椎动物寂寞激酶（VLK/Pkdcc）的突触前释放是EphB2和GluN1在突触上的直接胞外相互作用的必要和充分的，从而磷酸化EphB2的外结构域并介导损伤引起的疼痛。Pkdcc是神经系统的重要基因，VLK富集于突触，并以活性和可溶性N-乙基马来酰亚胺敏感因子激活蛋白受体（SNARE）依赖的方式从神经元释放，以驱动细胞外相互作用。他们的研究结果表明，突触前感觉神经元特异性VLK敲除可以减轻小鼠术后疼痛，但不会改变感觉运动表现，这表明VLK在损伤反应中对突触蛋白-蛋白相互作用和急性疼痛进行了关键调节。
据了解，数百个蛋白胞外结构域的磷酸化是由两个激酶家族介导的，但这些激酶的功能作用尚未得到充分探讨。
附：英文原文
Title: The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain
Author: Kolluru D. Srikanth, Hajira Elahi, Praveen Chander, Halley R. Washburn, Shayne Hassler, Juliet M. Mwirigi, Moeno Kume, Jessica Loucks, Rohita Arjarapu, Rachel Hodge, Lucy He, Khadijah Mazhar, Stephanie I. Shiers, Ishwarya Sankaranarayanan, Hediye Erdjument-Bromage, Thomas A. Neubert, Patrick M. Dougherty, Zachary T. Campbell, Raehum Paik, Theodore J. Price, Matthew B. Dalva
Issue&Volume: 2025-11-20
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.
DOI: adp1007
Source: https://www.science.org/doi/10.1126/science.adp1007