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dc.contributor.authorYeh, Chung-Yang
dc.contributor.authorBulas, Ashlyn M.
dc.contributor.authorMoutal, Aubin
dc.contributor.authorSaloman, Jami L.
dc.contributor.authorHartnett, Karen A.
dc.contributor.authorAnderson, Charles T.
dc.contributor.authorTzounopoulos, Thanos
dc.contributor.authorSun, Dandan
dc.contributor.authorKhanna, Rajesh
dc.contributor.authorAizenman, Elias
dc.date.accessioned2017-07-06T22:40:17Z
dc.date.available2017-07-06T22:40:17Z
dc.date.issued2017-06-07
dc.identifier.citationTargeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke 2017, 37 (23):5648 The Journal of Neuroscienceen
dc.identifier.issn0270-6474
dc.identifier.issn1529-2401
dc.identifier.doi10.1523/JNEUROSCI.3811-16.2017
dc.identifier.urihttp://hdl.handle.net/10150/624636
dc.description.abstractThe voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE(soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo. The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy.
dc.description.sponsorshipNational Institutes of Health [NS043277, DC007905, 5T32NS007433-18]; American Heart Association [16PRE29170009]en
dc.language.isoenen
dc.publisherSOC NEUROSCIENCEen
dc.relation.urlhttp://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.3811-16.2017en
dc.rightsCopyright © 2017 the authors.en
dc.subjectapoptosisen
dc.subjectischemiaen
dc.subjectneuroprotectionen
dc.subjectpotassium channelen
dc.subjectsyntaxinen
dc.subjectzincen
dc.titleTargeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Strokeen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Coll Med, Dept Pharmacol, Dept Anesthesiolen
dc.contributor.departmentUniv Arizona, Coll Med, Dept Grad Interdisciplinary Program Neuroen
dc.identifier.journalThe Journal of Neuroscienceen
dc.description.note6 month embargo; Published: 7 June 2017en
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2017-12-08T00:00:00Z
html.description.abstractThe voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE(soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo. The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy.


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