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Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis

Molecular Psychiatry volume 23, pages 1542–1554 (2018)Cite this article

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Abstract

Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Aβ, a central component of neuritic plaques in Alzheimer’s brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2.1 clustering on cell membrane, resulting in decreased Ik of Kv2.1 and a hyperpolarizing shift in primary neurons. Furthermore, we discovered that the BACE2-cleaved Kv2.1 forms, Kv2.1-1-375, Kv2.1-1-716, and Kv2.1-1-768, depressed the delayed rectifier Ik surge and reduced neuronal apoptosis. Our study suggests that BACE2 plays a neuroprotective role by cleavage of Kv2.1 to prevent the outward potassium currents, a potential new target for Alzheimer’s treatment.

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Acknowledgements

We thank Yu Tian Wang and Zhifang Dong for helpful discussions. This study was supported by the National Natural Science Foundation of China (NSFC) grant 81322014 (XS), and the Canadian Institutes of Health Research (CIHR) Operating Grant MOP-142487 (WS). WS is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease. YZ is the recipient of Michael Smith Foundation for Health Research Post-Doctoral Fellowship Award.

Author contributions

XS and WS conceived and designed the experiments; FL, YZ, ZL, QS, HL, JZhao, JX, JZheng, YY, and XY performed the experiments. FL, YZ, XY, XS and WS analyzed and contributed reagents /materials /analysis tools; FL, YZ, XS and WS wrote the paper. All authors reviewed the manuscript.

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    Authors and Affiliations

    1. Department of Neurology, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China

      Fuchen Liu, Zonglai Liang, Qianwen Sun, Jingwen Xu, Jinfan Zheng & Yan Yun

    2. Otolaryngology Key Lab of the Ministry of Health, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China

      Heng Liu, Juan Zhao & Xiulian Sun

    3. Brain Research Institute, Qilu hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China

      Xiulian Sun

    4. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

      Yun Zhang & Weihong Song

    5. Department of Physiology, Medical College of Shandong University, 44 Wenhuaxi Rd, 250012, Jinan, China

      Xiao Yu

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    1. Fuchen Liu
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    Liu, F., Zhang, Y., Liang, Z. et al. Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis. Mol Psychiatry 23, 1542–1554 (2018). https://doi.org/10.1038/s41380-018-0060-2

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