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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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© 2022 Published by Elsevier Inc.