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開催日 2014/9/11
時間 15:00 - 16:00
会場 Room J(313+314)
Chairperson(s) 小泉 修一 / Schuichi Koizumi (山梨大学大学院医学工学総合研究部薬理学講座 / Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan)
津田 誠 / Makoto Tsuda (九州大学大学院薬学研究院ライフイノベーション分野 / Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan)

Involvement of TRPC channels in sphingosine-1-phosphate-induced astrocytic responses

  • O1-J-4-4
  • 勝本 るみ / Rumi Katsumoto:1 白川 久志 / Hisashi Shirakawa:1 長島 卓也 / Takuya Nagashima:1 中川 貴之 / Takayuki Nakagawa:1,2 金子 周司 / Shuji Kaneko:1 
  • 1:京都大・薬・生体機能解析学 / Dept Mol Pharm, Kyoto Univ, Kyoto, Japan 2:京都大学医学部附属病院 薬剤部 / Dept Clin Pharmacol Ther, Kyoto Univ Hosp, Kyoto, Japan 

Astrocytes are the most abundant cells in the CNS and play diverse roles in the regulation of neuronal activity, vascular function, and gliotransmitter release. On the contrary, pathologically activated astrocytes have been reported to show astrogliosis, which can cause neuronal dysfunction in neurodegenerative diseases. A biologically active lipid, sphingosine-1-phosphate (S1P) is highly abundant in blood, and has an important role in regulating the growth, survival and migration of a variety of cells. Binding of the endogenous ligand S1P results in activation of various signaling pathways via the G protein-coupled receptors, some of which generates Ca2+ mobilization. In astrocyte, although S1P is reported to be involved in proliferation, migration, and Ca2+ signaling. the precise mechanisms underlying S1P-induced Ca2+ mobilization in astrocytes remain to be elucidated. Transient receptor potential canonical (TRPC) channels are Ca2+-permeable cation channels expressed in astrocytes and involved in Ca2+ influx after receptor stimulation. In this study, we investigated the involvement of TRPC channels in S1P-induced Ca2+ response and the subsequent astrocytic activation. In Ca2+ imaging experiments, application of S1P at 1 μM elicited a transient followed by sustained increase in intracellular Ca2+ concentration in rat cultured cortical astrocytes. The sustained Ca2+ response was markedly inhibited by a S1P2 receptor antagonist JTE013, a S1P3 receptor antagonist CAY10444 or a non-selective TRPC channel inhibitor, Pyr2. In addition, S1P induced secretion of CXCL1 protein, which was significantly suppressed by either treatment with the TRPC channels inhibitor Pyr2, inhibitors of Ca2+ signaling, or MAPK inhibitors. Taken together, S1P induced sustained Ca2+ elevation via Gq-coupled receptor S1P2 and S1P3, and the following Ca2+ entry through TRPC channel could activate MAPK signaling, which leads to the increased secretion of the pro-inflammatory or neuroprotective chemokine CXCL1 from astrocytes.

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