Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels

Anthony J. Schulie, Chung Yang Yeh, Bailey N. Orang, Olivia J. Pa, Madelynn P. Hopkin, Aubin Moutal, Rajesh Khanna, Dandan Sun, Jason A. Justic, Elias Aizenman

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Abstract

Kv2.1 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.

Original languageEnglish (US)
Article numbereaaz8110
JournalScience Advances
Volume6
Issue number27
DOIs
StatePublished - Jul 2020

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    Schulie, A. J., Yeh, C. Y., Orang, B. N., Pa, O. J., Hopkin, M. P., Moutal, A., Khanna, R., Sun, D., Justic, J. 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]. https://doi.org/10.1126/sciadv.aaz8110