Impairment of CaMKII activation and attenuation of neuropathic pain in mice lacking NR2B phosphorylated at Tyr1472

Autor:	Emiko Okuda-Ashitaka, Tayo Katano, Seiji Ito, Shunji Kunori, Tadashi Yamamoto, Shinji Matsumura, Tamaki Mabuchi, Masahiko Watanabe, Tetsuya Abe, Takanobu Nakazawa
Rok vydání:	2010
Předmět:	medicine.medical_specialty Chemistry musculoskeletal neural and ocular physiology General Neuroscience Glutamate receptor Long-term potentiation Nerve injury Endocrinology Nociception nervous system Internal medicine Ca2+/calmodulin-dependent protein kinase Synaptic plasticity Neuropathic pain medicine NMDA receptor medicine.symptom Neuroscience
Zdroj:	European Journal of Neuroscience. 32:798-810
ISSN:	0953-816X
DOI:	10.1111/j.1460-9568.2010.07348.x
Popis:	Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a key mediator of long-term potentiation (LTP), which can be triggered by N-methyl-d-aspartate (NMDA) receptor-mediated Ca(2+) influx. We previously demonstrated that Fyn kinase-mediated phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 in the dorsal horn was involved in a neuropathic pain state even 1 week after nerve injury. Here we show that Y1472F-KI mice with a knock-in mutation of the Tyr1472 site to phenylalanine did not exhibit neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses and induction of inflammatory pain. Phosphorylation of NR2B at Tyr1472 was only impaired in the spinal cord of Y1472F-KI mice among the major phosphorylation sites. There was no difference in the Ca(2+) response to glutamate and sensitivity to NMDA receptor antagonists between naive wild-type and Y1472F-KI mice, and the Ca(2+) response to glutamate was attenuated in the Y1472F-KI mice after nerve injury. Autophosphorylation of CaMKII at Thr286 was markedly impaired in Y1472F-KI mice after nerve injury, but there was no difference in phosphorylation of CaMKII at Thr305 or protein kinase Cγ at Thr674, and activation of neuronal nitric oxide synthase and microglia in the superficial layer of spinal cord between wild-type and Y1472F-KI mice after the operation. These results demonstrate that the attenuation of neuropathic pain is caused by the impaired NMDA receptor-mediated CaMKII signaling in Y1472F-KI mice, and suggest that autophosphorylation of CaMKII at Thr286 plays a central part not only in LTP, but also in persistent neuropathic pain.
Databáze:	OpenAIRE
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