Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels
AuthorSchulien, Anthony J.
Orange, Bailey N.
Pav, Olivia J.
Hopkins, Madelynn P.
Justice, Jason A.
AffiliationUniv Arizona, Coll Med, Dept Pharmacol
MetadataShow full item record
PublisherAMER ASSOC ADVANCEMENT SCIENCE
CitationSchulien, A. J., Yeh, C. Y., Orange, B. N., Pav, O. J., Hopkins, M. P., Moutal, A., ... & Aizenman, E. (2020). Targeted disruption of Kv2. 1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2. 1 channels. Science advances, 6(27), eaaz8110.
RightsCopyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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AbstractKv2.1 channels mediate cell death-enabling loss of cytosolic potassium in neurons following plasma membrane insertion at somatodendritic clusters. Overexpression of the carboxyl terminus (CT) of the cognate channel Kv2.2 is neuroprotective by disrupting Kv2.1 surface clusters. Here, we define a seven-amino acid declustering domain within Kv2.2 CT (DP-2) and demonstrate its neuroprotective efficacy in a murine ischemia-reperfusion model. TAT-DP-2, a membrane-permeable derivative, induces Kv2.1 surface cluster dispersal, prevents post-injurious pro-apoptotic potassium current enhancement, and is neuroprotective in vitro by disrupting the association of Kv2.1 with VAPA. TAT-DP-2 also induces Kv2.1 cluster dispersal in vivo in mice, reducing infarct size and improving long-term neurological function following stroke. We suggest that TAT-DP-2 induces Kv2.1 declustering by disrupting Kv2.1-VAPA association and scaffolding sites required for the membrane insertion of Kv2.1 channels following injury. We present the first evidence of targeted disruption of Kv2.1-VAPA association as a neuroprotective strategy following brain ischemia.
NoteOpen access journal
VersionFinal published version
SponsorsNational Institutes of Health
Except where otherwise noted, this item's license is described as Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).