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

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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Correspondence to Weihong Song or Xiulian Sun.

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These authors contributed equally: Fuchen Liu, Yun Zhang.

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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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