Alleviation by GABA B Receptors of Neurotoxicity Mediated by Mitochondrial Permeability Transition Pore in Cultured Muri
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ORIGINAL PAPER
Alleviation by GABAB Receptors of Neurotoxicity Mediated by Mitochondrial Permeability Transition Pore in Cultured Murine Cortical Neurons Exposed to N-Methyl-d-aspartate Toshihiko Kinjo1 · Yoshino Ashida1 · Hiroshi Higashi1 · Satoshi Sugimura2 · Miho Washida2 · Hiroki Niihara2 · Kiyokazu Ogita2 · Yukio Yoneda3 · Nobuyuki Kuramoto1
Received: 11 April 2017 / Revised: 19 May 2017 / Accepted: 24 May 2017 © Springer Science+Business Media New York 2017
Abstract Mitochondrial permeability transition pore (PTP) is supposed to at least in part participate in molecular mechanisms underlying the neurotoxicity seen after overactivation of N-methyl-d-aspartate (NMDA) receptor (NMDAR) in neurons. In this study, we have evaluated whether activation of GABAB receptor (GABABR), which is linked to membrane G protein-coupled inwardlyrectifying K+ ion channels (GIRKs), leads to protection of the NMDA-induced neurotoxicity in a manner relevant to mitochondrial membrane depolarization in cultured embryonic mouse cortical neurons. The cationic fluorescent dye 3,3′-dipropylthiacarbocyanine was used for determination of mitochondrial membrane potential. The PTP opener salicylic acid induced a fluorescence increase with a vitality decrease in a manner sensitive to the PTP inhibitor ciclosporin, while ciclosporin alone was effective in significantly preventing both fluorescence increase and viability decrease by NMDA as seen with an NMDAR antagonist. The NMDA-induced fluorescence increase and viability decrease were similarly prevented by pretreatment with the GABABR agonist baclofen, but not by the GABAAR agonist muscimol, in a fashion sensitive to a GABABR antagonist. Moreover, the GIRK inhibitor tertiapin canceled the * Nobuyuki Kuramoto [email protected] 1
Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45‑1 Nagaotoge‑cho, Hirakata, Osaka 573‑0101, Japan
2
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573‑0101, Japan
3
Section of Prophylactic Pharmacology, Venture Business Laboratory, Kanazawa University, Kanazawa 920‑1192, Japan
inhibition by baclofen of the NMDA-induced fluorescence increase. These results suggest that G ABABR rather than GABAAR is protective against the NMDA-induced neurotoxicity mediated by mitochondrial PTP through a mechanism relevant to opening of membrane GIRKs in neurons. Keywords GABABR · GIRKs · NMDAR · Mitochondrial depolarization · Cell death · Tertiapin Abbreviations AC Adenylyl cyclase AUC Area under curve DiSC3(5) 3,3′-Dipropylthiacarbocyanine iodide DIV Days in vitro GABA γ-Aminobutyric acid GABAAR γ-Aminobutyric acid A receptor GABABR γ-Aminobutyric acid B receptor GIRK G protein-coupled inwardly-rectifying K+ ion channel GPCR G protein-coupled receptor MTT 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide NMDA N-Methyl-d-aspartate NMDAR N-Methyl-d-aspartate receptor MK-801 Dizocilpine PKA Protein kinase A PTP Perme
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