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Mol Psychiatry. 2018 Jul;23(7):1542-1554. doi: 10.1038/s41380-018-0060-2. Epub 2018 Apr 27.

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

Author information

1
Department of Neurology, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China.
2
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
3
Otolaryngology Key Lab of the Ministry of Health, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China.
4
Department of Physiology, Medical College of Shandong University, 44 Wenhuaxi Rd, 250012, Jinan, China.
5
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. weihong@mail.ubc.ca.
6
Otolaryngology Key Lab of the Ministry of Health, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China. xiulians@gmail.com.
7
Brain Research Institute, Qilu hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China. xiulians@gmail.com.

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.

PMID:
29703946
DOI:
10.1038/s41380-018-0060-2

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