Arizona Health Sciences

Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke.

TitleTargeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke.
Publication TypeJournal Article
Year of Publication2017
AuthorsYeh C-Y, Bulas AM, Moutal A, Saloman JL, Hartnett KA, Anderson CT, Tzounopoulos T, Sun D, Khanna R, Aizenman E
JournalJ Neurosci
Volume37
Issue23
Pagination5648-5658
Date Published2017 Jun 07
ISSN1529-2401
Abstract

The 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 Zn(2+)-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.SIGNIFICANCE STATEMENT Kv2.1 is a critical regulator of apoptosis in central neurons. It has not been determined, however, whether the cell death-enabling function of this K(+) channel can be selectively targeted to improve neuronal survival following injury in vivo The experiments presented here demonstrate that the cell death-specific role of Kv2.1 can be uniquely modulated to provide neuroprotection in an animal model of acute ischemic stroke. We thus reveal a novel therapeutic strategy for neurological disorders that are accompanied by Kv2.1-facilitated forms of cell death.

DOI10.1523/JNEUROSCI.3811-16.2017
Alternate JournalJ. Neurosci.
PubMed ID28483976
PubMed Central IDPMC5469303
Grant ListR01 DC007905 / DC / NIDCD NIH HHS / United States
R01 NS043277 / NS / NINDS NIH HHS / United States
R56 NS043277 / NS / NINDS NIH HHS / United States
T32 NS007433 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Rajesh Khanna