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

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 blood-brain 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-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents fo

SUBMITTER: Yeh CY 

PROVIDER: S-EPMC6681760 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature