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EphB/ephrinB signaling plays a key role in synaptic function and is linked to several neuropathological conditions, including neuropathic pain. The EphB2 receptor tyrosine kinase is known to interact with N-Methyl-D-aspartate glutamate receptors (NMDAR), resulting in increased surface retention of NMDARs at the synapse and an enhancement of postsynaptic currents. As changes in NMDAR signaling have been heavily implicated in the development of both acute and chronic pain, targeting this receptor interaction may produce clinically relevant therapeutics. We have recently demonstrated that the phosphorylation of a tyrosine residue (Y504) on the extracellular domain of the EphB2 receptor is necessary and sufficient to induce its interaction with NMDARs and cause mechanical pain hypersensitivity. The kinase responsible for this phosphorylation is unknown. We hypothesized that Vertebrate Lonesome Kinase (VLK) may be the key effector. Since the phosphorylation site of interest is located on the extracellular face of the EphB2 receptor, a secreted tyrosine kinase like VLK is an ideal candidate. Our results provide strong support for our hypothesis that VLK drives pain via extracellular phosphorylation of EphBs. We show that intrathecal injection of VLK resulted in long-lasting mechanical hypersensitivity in mice. Additionally, the effects observed for VLK were dependent on kinase activity and entirely dependent upon NMDARs because they were blocked by AP-5. We also show evidence of VLK protein and mRNA expression in dorsal root ganglion and spinal cord neurons of both mice and humans. Our results provide evidence for the involvement of VLK in pain behaviors and spinal cord NMDAR signaling, and identify a completely unique extracellular kinase target for the alleviation of pain. Grant support from NIH grants NS111976 & NS115441.
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