Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke

Journal	Proc. Natl. Acad. Sci. U. S. A. 118(32):e2018850118 (2021)
Title	Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke
Laboratory	Cellular and Molecular Neurobiology Group

Abstract

Stroke is the second leading cause of death and the most frequent cause of disability in adults. After stroke, most ischemic neurons die and a few neurons live, leading to brain dysfunction; yet, genes involved in both neuronal survival and death remain poorly understood. Here, we found that the activity-dependent transcription factor Npas4 is essential for acquisition of neuronal tolerance to ischemia. Moreover, a systematic search for Npas4-downstream genes identified Gem, which encodes Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of voltage-gated Ca²⁺ channels to inhibit excess Ca²⁺ influx, thereby protecting neurons from excitotoxic death. Our findings suggest that Gem expression via Npas4 promotes neuroprotection and neuroplasticity in injured and healthy brains, respectively.

Authors	Hiroo Takahashi (1, 2), Ryo Asahina (2), Masayuki Fujioka (2), Takeshi K. Matsui (3), Shigeki Kato (4), Eiichiro Mori (3), Hiroyuki Hioki (5), Tohru Yamamoto (1), Kazuto Kobayashi (4), Akio Tsuboi (2, 6) Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan Laboratory for Molecular Biology of Neural Systems, Advanced Medical Research Center, Nara Medical University, Nara 634-8521, Japan Department of Future Basic Medicine, School of Medicine, Nara Medical University, Nara 634-8521, Japan Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima 960-1295, Japan Department of Cell Biology and Neuroscience, School of Medicine, Juntendo University, Tokyo 113-8421, Japan Laboratory for Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan
PubMed	34349016

Authors

Hiroo Takahashi (1, 2), Ryo Asahina (2), Masayuki Fujioka (2), Takeshi K. Matsui (3), Shigeki Kato (4), Eiichiro Mori (3), Hiroyuki Hioki (5), Tohru Yamamoto (1), Kazuto Kobayashi (4), Akio Tsuboi (2, 6)

Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan
Laboratory for Molecular Biology of Neural Systems, Advanced Medical Research Center, Nara Medical University, Nara 634-8521, Japan
Department of Future Basic Medicine, School of Medicine, Nara Medical University, Nara 634-8521, Japan
Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima 960-1295, Japan
Department of Cell Biology and Neuroscience, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
Laboratory for Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan

PubMed

34349016