title: Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain.
abstract: Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Abe
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumura
authors.forename: Tayo
authors.initials: T
authors.lastname: Katano
authors.forename: Tamaki
authors.initials: T
authors.lastname: Mabuchi
authors.forename: Kunio
authors.initials: K
authors.lastname: Takagi
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hattori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yagi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakai
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D015232:Dinoprostone / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006651:Histocytochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009363:Neoplasm Proteins; D009569:Nitric Oxide / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology* / Q000523:psychology; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: C121001:NR2B NMDA receptor; D009363:Neoplasm Proteins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D014443:Tyrosine; C095106:traxoprodil mesylate; D011505:Protein-Tyrosine Kinases; C490512:Frk protein, mouse; D019061:src-Family Kinases; D015232:Dinoprostone