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, Tetsuya Terasaki

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)192-200
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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