Title: Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic.

Authors: Ali, Syed R; Liu, Zhiqing; Nenov, Miroslav N; Folorunso, Oluwarotimi; Singh, Aditya; Scala, Federico; Chen, Haiying; James, T F; Alshammari, Musaad; Panova-Elektronova, Neli I; White, Mark Andrew; Zhou, Jia; Laezza, Fernanda

Published In ACS Chem Neurosci, (2018 05 16)

Abstract: Protein-protein interactions (PPI) offer unexploited opportunities for CNS drug discovery and neurochemical probe development. Here, we present ZL181, a novel peptidomimetic targeting the PPI interface of the voltage-gated Na+ channel Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). ZL181 binds to FGF14 and inhibits its interaction with the Nav1.6 channel C-tail. In HEK-Nav1.6 expressing cells, ZL181 acts synergistically with FGF14 to suppress Nav1.6 current density and to slow kinetics of fast inactivation, but antagonizes FGF14 modulation of steady-state inactivation that is regulated by the N-terminal tail of the protein. In medium spiny neurons in the nucleus accumbens, ZL181 suppresses excitability by a mechanism that is dependent upon expression of FGF14 and is consistent with a state-dependent inhibition of FGF14. Overall, ZL181 and derivatives could lay the ground for developing allosteric modulators of Nav channels that are of interest for a broad range of CNS disorders.

PubMed ID: 29359916

MeSH Terms: Animals; Fibroblast Growth Factors/genetics; Fibroblast Growth Factors/pharmacology*; HEK293 Cells; Hippocampus/drug effects*; Humans; Mice, Knockout; Peptidomimetics/pharmacology; Sodium/metabolism*; Voltage-Gated Sodium Channels/drug effects*