EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

Wu HC, Chang CH, Peng HY, Chen GD, Lai CY, Hsieh MC, Lin TB. EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B. Am J Physiol Renal Physiol 300: F403-F411, 2011. First published December 8, 2010; doi:10.1152/ajprenal.00520.2010.-Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in pain-related neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-D-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L-6-S-2) dorsal horn in response to intrathecal ephrinB2 injections. When compared with vehicle solution, exogenous ephrinB2 (5 mu g/rat it)-induced reflex potentiation, in associated with phosphorylation of EphB1/2, Src-family kinase, NR2B Y1336 and Y1472 tyrosine residues. Both intrathecal EphB1 and EphB2 immunoglobulin fusion protein (both 10 mu g/rat it) prevented ephrinB2-dependent reflex potentiation, as well as protein phosphorylation. Pretreatment with PP2 (50 mu M, 10 mu l it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-D-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area.