Defining the Kv2.1-syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant

Chung Yang Yeh, Zhaofeng Ye, Aubin Moutal, Shivani Gaur, Amanda M. Henton, Stylianos Kouvaros, Jami L. Saloman, Karen A. Hartnett-Scott, Thanos Tzounopoulos, Rajesh Khanna, Elias Aizenman, Carlos J. Camacho

Research output: Contribution to journalArticle

Abstract

The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and bloodbrain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxinbinding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.

Original languageEnglish (US)
Pages (from-to)15696-15705
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number31
DOIs
StatePublished - Jul 30 2019

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Keywords

  • Kv2.1
  • Neurodegeneration
  • Neuroprotection
  • Syntaxin

ASJC Scopus subject areas

  • General

Cite this

Yeh, C. Y., Ye, Z., Moutal, A., Gaur, S., Henton, A. M., Kouvaros, S., Saloman, J. L., Hartnett-Scott, K. A., Tzounopoulos, T., Khanna, R., Aizenman, E., & Camacho, C. J. (2019). Defining the Kv2.1-syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant. Proceedings of the National Academy of Sciences of the United States of America, 116(31), 15696-15705. https://doi.org/10.1073/pnas.1903401116