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Research ArticleMetabolism, Transport, and Pharmacogenomics

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

Yosuke Kaneko, Masanori Tachikawa, Ryo Akaogi, Kazuhisa Fujimoto, Megumi Ishibashi, Yasuo Uchida, Pierre-Olivier Couraud, Sumio Ohtsuki, Ken-ichi Hosoya and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics April 2015, 353 (1) 192-200; DOI: https://doi.org/10.1124/jpet.114.220210
Yosuke Kaneko
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Masanori Tachikawa
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Ryo Akaogi
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Kazuhisa Fujimoto
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Megumi Ishibashi
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Yasuo Uchida
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Pierre-Olivier Couraud
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Sumio Ohtsuki
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Ken-ichi Hosoya
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Tetsuya Terasaki
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.K., M.T., R.A., Y.U., T.T.); Department of Applied Chemistry and Biochemistry, Faculty of Engineering, Kyushu Sangyo University, Fukuoka, Japan (K.F., M.I.); INSERM, U1016, Institut Cochin and CNRS, UMR8104, and Université Paris Descartes, Paris, France (P.-O.C.); Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan (S.O.); and Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (K.H.)
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Abstract

Dysregulation of blood-brain barrier (BBB) transport function is thought to exacerbate neuronal damage in acute ischemic stroke. The purpose of this study was to clarify the characteristics of pannexin (Px) and/or connexin (Cx) hemichannel(s)-mediated transport of organic anions and cations in human BBB endothelial cell line hCMEC/D3 and to identify inhibitors of hemichannel opening in hCMEC/D3 cells in the absence of extracellular Ca2+, a condition mimicking acute ischemic stroke. In the absence of extracellular Ca2+, the cells showed increased uptake and efflux transport of organic ionic fluorescent dyes. Classic hemichannel inhibitors markedly inhibited the enhanced uptake and efflux. Quantitative targeted absolute proteomics confirmed Px1 and Cx43 protein expression in plasma membrane of hCMEC/D3 cells. Knockdown of Px1 and Cx43 with the small interfering RNAs significantly inhibited the enhanced uptake and efflux of organic anionic and cationic fluorescent dyes. Clinically used cilnidipine and progesterone, which have neuroprotective effects in animal ischemia models, were identified as inhibitors of hemichannel opening. These findings suggest that altered transport dynamics at the human BBB in the absence of extracellular Ca2+ is at least partly attributable to opening of Px1 and Cx43 hemichannels. Therefore, we speculate that Px1 and Cx43 may be potential drug targets to ameliorate BBB transport dysregulation during acute ischemia.

Footnotes

    • Received September 29, 2014.
    • Accepted February 9, 2015.
  • This study was supported in part by four Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) for Young Scientists (A) [KAKENHI: 23790170] and for Scientific Research (A) [KAKENHI: 24249011]; and by the JSPS and Centre National de la Recherche Scientifique (CNRS) under the Japan-France Basic Scientific Cooperation Program. T.T. and S.O. are full professors at Tohoku University and Kumamoto University, respectively, and are also directors of Proteomedix Frontiers Co. Ltd. This study was not supported by Proteomedix Frontiers Co. Ltd., and their positions at Proteomedix Frontiers Co. Ltd. did not affect the design of the study, the collection, analysis, and interpretation of the data, the writing of the manuscript, or the decision to publish, and does not present any financial conflicts. The remaining authors declare no competing financial interests.

  • dx.doi.org/10.1124/jpet.114.220210.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 1
1 Apr 2015
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Pannexin 1 and Connexin 43 in Human Brain Endothelial Cells

Yosuke Kaneko, Masanori Tachikawa, Ryo Akaogi, Kazuhisa Fujimoto, Megumi Ishibashi, Yasuo Uchida, Pierre-Olivier Couraud, Sumio Ohtsuki, Ken-ichi Hosoya and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 192-200; DOI: https://doi.org/10.1124/jpet.114.220210

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Pannexin 1 and Connexin 43 in Human Brain Endothelial Cells

Yosuke Kaneko, Masanori Tachikawa, Ryo Akaogi, Kazuhisa Fujimoto, Megumi Ishibashi, Yasuo Uchida, Pierre-Olivier Couraud, Sumio Ohtsuki, Ken-ichi Hosoya and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 192-200; DOI: https://doi.org/10.1124/jpet.114.220210
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