VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain.
VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain.
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VLK 驱动 EphB2 的细胞外磷酸化，以控制 EphB2-NMDAR 相互作用和损伤引起的疼痛。
DOI：
10.1101/2024.03.18.585314
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Neuber
中科院分区：
文献类型：
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作者：
Srikanth,KolluruD;Elahi,Hajira;Chander,Praveen;Washburn,HalleyR;Hassler,Shayne;Mwirigi,JulietM;Kume,Moeno;Loucks,Jessica;Arjarapu,Rohita;Hodge,Rachel;Shiers,StephanieI;Sankaranarayanan,Ishwarya;Erdjument-Bromage,Hediye;Neuber
数百个蛋白质胞外结构域的磷酸化是由两个激酶家族介导的，但这些激酶的重要性尚未得到充分探索。在这里，我们发现酪氨酸定向胞外激酶、脊椎动物孤独激酶 (VLK/Pkdcc) 的突触前释放对于 EphB2 和 GluN1 在突触处的直接细胞外相互作用、EphB2 胞外域的磷酸化以及损伤引起的疼痛是必要且充分的。 Pkdcc 是神经系统中的必需基因，VLK 存在于突触小泡中，并以 SNARE 依赖性方式从神经元中释放。 VLK 由伤害性感觉神经元表达，其中突触前感觉神经元特异性敲除使小鼠不受术后疼痛影响，且不改变本体感觉。 VLK 定义了一种细胞外机制，可调节蛋白质-蛋白质相互作用和非阿片类药物依赖性疼痛以应对损伤。
Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, 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 for injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury.