The importance of CRAC channels in astrocytes as the mechanism of isoflurane anesthesia

• Project/Area Number: 18K16490
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Osaka City University
• Principal Investigator: Hori Kotaro 大阪市立大学, 大学院医学研究科, 講師 (60735827)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 麻酔 / CRACチャネル / パッチクランプ法 / カルシウム / 抑制性神経細胞 / ノックアウトマウス / 人工授精 / アストロサイト

Outline of Final Research Achievements

In this study, CRAC channels in hippocampal inhibitory neurons were shown to play important roles in the mechanism of memory deficit immediately after general anesthesia. We found that CRAC channels in inhibitory neurons on the border between CA1 stratum lacunosum moleculare and stratum radiatum regulate action potential generation induced by sevoflurane anesthesia, which may result in less memory deficit in interneuron-specific knock out mice of Orai1, the pore of CRAC channels.

Academic Significance and Societal Importance of the Research Achievements

全身麻酔薬の作用機序は未だ不明な点も多いが、中でも全身麻酔後の短期記憶障害は術後せん妄や認知機能障害との関わりが示唆されているため、臨床上非常に重要なテーマである。今回、我々の研究からセボフルラン麻酔による短期記憶障害の作用機序として、海馬抑制性神経細胞におけるCRACチャネルが重要な役割を果たしている可能性が示唆された。さらなる詳細な作用機序等が解明されれば、現在米国で臨床試験がなされているCRACチャネル阻害薬の臨床応用等、今後の発展が期待される。

Research Products

• [Journal Article] Orai1 Channels Are Essential for Amplification of Glutamate-Evoked Ca2+ Signals in Dendritic Spines to Regulate Working and Associative Memory (2020)
  • Author(s): Maneshi Mohammad Mehdi、Toth Anna B.、Ishii Toshiyuki、Hori Kotaro、Tsujikawa Shogo、Shum Andrew K.、Shrestha Nisha、Yamashita Megumi、Miller Richard J.、Radulovic Jelena、Swanson Geoffrey T.、Prakriya Murali
  • Journal Title: Cell Reports Volume: 33 Issue: 9 Pages: 108464-108464
  • DOI: 10.1016/j.celrep.2020.108464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of chemoconvulsant‐induced seizures by store‐operated Orai1 channels (2020)
  • Author(s): Hori Kotaro、Tsujikawa Shogo、Novakovic Michaela M.、Yamashita Megumi、Prakriya Murali
  • Journal Title: The Journal of Physiology Volume: 598 Issue: 23 Pages: 5391-5409
  • DOI: 10.1113/jp280119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Left Ventricular Hypertrophy Increases Susceptibility to Bupivacaine-induced Cardiotoxicity through Overexpression of Transient Receptor Potential Canonical Channels in Rats (2020)
  • Author(s): Hideki Hino, Tadashi Matsuura, Miyuki Kuno, Kotaro Hori, Shogo Tsujikawa, Takashi Mori, Kiyonobu Nishikawa
  • Journal Title: Anesthesiology Volume: 133 Issue: 5 Pages: 1077-1092
  • DOI: 10.1097/aln.0000000000003554
  • Peer Reviewed / Open Access
• [Journal Article] CRAC channels regulate astrocyte Ca2+ signaling and gliotransmitter release to modulate hippocampal GABAergic transmission (2019)
  • Author(s): Toth Anna B.、Hori Kotaro、Novakovic Michaela M.、Bernstein Natalie G.、Lambot Laurie、Prakriya Murali
  • Journal Title: Science Signaling Volume: 12 Issue: 582
  • DOI: 10.1126/scisignal.aaw5450
  • Peer Reviewed / Open Access / Int'l Joint Research