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TRPM7 Mediates Neuronal Cell Death Upstream of Calcium/Calmodulin-Dependent Protein Kinase II and Calcineurin Mechanism in Neonatal Hypoxic-Ischemic Brain Injury

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Abstract

Transient receptor potential melastatin 7 (TRPM7), a calcium-permeable, ubiquitously expressed ion channel, is critical for axonal development, and mediates hypoxic and ischemic neuronal cell death in vitro and in vivo. However, the downstream mechanisms underlying the TRPM7-mediated processes in physiology and pathophysiology remain unclear. In this study, we employed a mouse model of hypoxic-ischemic brain cell death which mimics the pathophysiology of hypoxic-ischemic encephalopathy (HIE). HIE is a major public health issue and an important cause of neonatal deaths worldwide; however, the available treatments for HIE remain limited. Its survivors face life-long neurological challenges including mental retardation, cerebral palsy, epilepsy and seizure disorders, motor impairments, and visual and auditory impairments. Through a proteomic analysis, we identified calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphatase calcineurin as potential mediators of cell death downstream from TRPM7 activation. Further analysis revealed that TRPM7 mediates cell death through CaMKII, calmodulin, calcineurin, p38, and cofilin cascade. In vivo, we found a significant reduction of brain injury and improvement of short- and long-term functional outcomes after HI after administration of specific TRPM7 blocker waixenicin A. Our data demonstrate a molecular mechanism of TRPM7-mediated cell death and identifies TRPM7 as a promising therapeutic and drug development target for HIE.

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Abbreviations

TRPM7 channel:

Transient receptor potential melastatin 7 channel

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Acknowledgments

We thank S Huang for his technical assistance.

Funding

This work was supported by the following grants: NIH NIGMS P20 (GM103466) to FDH; Hamamatsu/Queen’s PET Imaging, LLC to AF; Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants to ZPF (RGPIN-2014-06471) and to HSS (RGPIN-2016-04574); NSERC Alexander Graham Bell Canada Graduate Scholarship to ET; NSERC Postgraduate Scholarship-Doctoral to RW.

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  1. Ekaterina Turlova and Raymond Wong contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada

    Ekaterina Turlova, Raymond Wong, Baofeng Xu, Feiya Li, Lida Du & Hong-Shuo Sun

  2. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada

    Ekaterina Turlova, Raymond Wong, Baofeng Xu, Feiya Li, Lida Du, Steven Habbous, Zhong-Ping Feng & Hong-Shuo Sun

  3. Department of Natural Sciences, Hawaii Pacific University, Kaneohe, HI, 96744, USA

    F. David Horgen

  4. Center for Biomedical Research at The Queen’s Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96720, USA

    Andrea Fleig

  5. Department of Pharmacology, University of Toronto, 1 King’s College Circle, Toronto, M5S 1A8, Canada

    Hong-Shuo Sun

  6. Leslie Dan Faculty of Pharmacy, University of Toronto, University of Toronto, Toronto, Canada

    Hong-Shuo Sun

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  1. Ekaterina Turlova
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Turlova, E., Wong, R., Xu, B. et al. TRPM7 Mediates Neuronal Cell Death Upstream of Calcium/Calmodulin-Dependent Protein Kinase II and Calcineurin Mechanism in Neonatal Hypoxic-Ischemic Brain Injury. Transl. Stroke Res. 12, 164–184 (2021). https://doi.org/10.1007/s12975-020-00810-3

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