title: Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury.
abstract: Maintenance of neuropathic pain caused by peripheral nerve injury crucially depends on the phosphorylation of GluN2B, a subunit of the N-methyl-d-aspartate (NMDA) receptor, at Tyr1472 (Y1472) and subsequent formation of a postsynaptic density (PSD) complex of superficial spinal dorsal horn neurons. Here we took advantage of comparative proteomic analysis based on isobaric stable isotope tags (iTRAQ) between wild-type and knock-in mice with a mutation of Y1472 to Phe of GluN2B (Y1472F-KI) to search for PSD proteins in the spinal dorsal horn that mediate the signaling downstream of phosphorylated Y1472 GluN2B. Among several candidate proteins, we focused on brain-enriched guanylate kinase-associated protein (BEGAIN), which was specifically up-regulated in wild-type mice after spared nerve injury (SNI). Immunohistochemical analysis using the generated antibody demonstrated that BEGAIN was highly localized at the synapse of inner lamina II in the spinal dorsal horn and that its expression was up-regulated after SNI in wild-type, but not in Y1472F-KI, mice. In addition, alteration of the kinetics of evoked excitatory postsynaptic currents for NMDA but not those for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in spinal lamina II was demonstrated by BEGAIN deletion. We demonstrated that mechanical allodynia, a condition of abnormal pain induced by innocuous stimuli, in the SNI model was significantly attenuated in BEGAIN-deficient mice. However, there was no significant difference between naive wild-type and BEGAIN-knockout mice in terms of physiological threshold for mechanical stimuli. These results suggest that BEGAIN was involved in pathological pain transmission through NMDA receptor activation by the phosphorylation of GluN2B at Y1472 in spinal inner lamina II.
authors: Department of Medical Chemistry, Kansai Medical University , Hirakata 573-1010, Japan.
authors: Tayo
authors: 0000-0002-7969-744X
authors: T
authors: Katano
authors: Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University , Suita 565-0871, Japan.
authors: Masafumi
authors: M
authors: Fukuda
authors: Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences , Okazaki 444-8787, Japan.
authors: Hidemasa
authors: H
authors: Furue
authors: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Neurology, University of California, San Francisco, CA 94158.
authors: Maya
authors: 0000-0002-3102-9071
authors: M
authors: Yamazaki
authors: Department of Cellular Neurobiology, Brain Research Institute, Niigata University , Niigata 951-8585, Japan.
authors: Manabu
authors: M
authors: Abe
authors: Department of Anatomy, Hokkaido University School of Medicine , Sapporo 060-8638, Japan.
authors: Masahiko
authors: 0000-0001-5037-7138
authors: M
authors: Watanabe
authors: Department of Medical Chemistry, Kansai Medical University , Hirakata 573-1010, Japan.
authors: Kazuhiko
authors: K
authors: Nishida
authors: Department of Medical Chemistry, Kansai Medical University, Hirakata 573-1010, Japan; Department of Optical Imaging, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors: Ikuko
authors: I
authors: Yao
authors: Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences , Okazaki 444-8787, Japan.
authors: Akihiro
authors: A
authors: Yamada
authors: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University , Tokyo 113-8519, Japan.
authors: Yutaka
authors: 0000-0003-1304-5286
authors: Y
authors: Hata
authors: Laboratory of Homeostatic Integration, Institute for Protein Research, Osaka University , Suita 565-0871, Japan.
authors: Nobuaki
authors: N
authors: Okumura
authors: Drug Innovation Center, Graduate School of Pharmaceutical Science, Osaka University , Suita, 565-0871, Japan.
authors: Takanobu
authors: T
authors: Nakazawa
authors: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University , Okinawa 904-0495, Japan.
authors: Tadashi
authors: T
authors: Yamamoto
authors: Department of Cellular Neurobiology, Brain Research Institute, Niigata University , Niigata 951-8585, Japan.
authors: Kenji
authors: K
authors: Sakimura
authors: Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University , Suita 565-0871, Japan.
authors: Toshifumi
authors: T
authors: Takao
authors: Department of Medical Chemistry, Kansai Medical University , Hirakata 573-1010, Japan.
authors: Seiji
authors: S
authors: Ito
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D015870:Gene Expression; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020543:Proteome; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014110:Touch
chemical_list: C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D020543:Proteome; D016194:Receptors, N-Methyl-D-Aspartate; D000074407:SAP90-PSD95 Associated Proteins
keywords: BEGAIN; GluN2B; neuropathic pain; postsynaptic density; proteomics; spinal lamina II