Publications (3)0 Total impact
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Youichi Shinozaki,
Koji Sumitomo,
Makoto Tsuda,
Schuichi Koizumi,
Kazuhide Inoue,
Keiichi Torimitsu,
陽一 篠崎,
弘二 住友,
誠 津田,
修一 小泉,
和秀 井上,
慶一 鳥光,
ヨウイチ シノザキ,
コウジ スミトモ,
マコト ツダ,
シュウイチ コイズミ, カズヒデ イノウエ,
ケイイチ トリミツ
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ABSTRACT: 受容体の時間的な形状変化を観察することに成功 : ATP受容体の構造変化メカニズムを解明(2009.04.30 九州大学プレスリリース) The ATP-gated P2X_4 receptor is a cation channel, which is important in various pathophysiological events. The architecture of the P2X_4 receptor in the activated state and how to change its structure in response to ATP binding are not fully understood. Here, we analyze the architecture and ATP-induced structural changes in P2X_4 receptors using fast-scanning atomic force microscopy (AFM). AFM images of the membrane-dissociated and membrane-inserted forms of P2X_4 receptors and a functional analysis revealed that P2X_4 receptors have an upward orientation on mica but lean to one side. Time-lapse imaging of the ATP-induced structural changes in P2X_4 receptors revealed two different forms of activated structures under 0 Ca^(2+) conditions, namely a trimer structure and a pore dilation-like tripartite structure. A dye uptake measurement demonstrated that ATP-activated P2X_4 receptors display pore dilation in the absence of Ca^(2+). With Ca^(2+), the P2X_4 receptors exhibited only a disengaged trimer and no dye uptake was observed. Thus our data provide a new insight into ATP-induced structural changes in P2X_4 receptors that correlate with pore dynamics.
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Makoto Tsuda,
Takahiro Masuda,
Junko Kitano,
Hiroshi Shimoyama,
Hidetoshi Tozaki-Saitoh,
Kazuhide Inoue,
誠 津田,
隆博 増田,
順子 北野,
裕 下山,
秀俊 齊藤,
和秀 井上,
マコト ツダ,
タカヒロ マスダ,
ジュンコ キタノ,
ヒロシ シモヤマ,
ヒデトシ トザキ-サイトウ, カズヒデ イノウエ
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ABSTRACT: 神経因性疼痛の発症メカニズムの最も基盤的な事実を解明 : インターフェロンγが最悪の難治性疼痛である神経因性疼痛を引き起こしていた(2009.04.16 九州大学プレスリリース) Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-γ (IFN-γR) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-γR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-γ-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X4 receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-γR-dependent microglial and behavioral alterations. These results suggest that IFN-γR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.
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