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

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

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)976-987
Number of pages12
JournalACS Chemical Neuroscience
Volume9
Issue number5
DOIs
StatePublished - May 16 2018

Keywords

  • CNS drug discovery
  • Fibroblast growth factor 14 (FGF14)
  • minimal functional domains
  • neurochemical probes
  • peptidomimetics
  • protein:protein interaction (PPI)
  • voltage-gated sodium channels (Nav1.6)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Fingerprint Dive into the research topics of 'Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic'. Together they form a unique fingerprint.

  • Cite this

    Ali, S. R., Liu, Z., Nenov, M., Folorunso, O., Singh, A., Scala, F., Chen, H., James, T. F., Alshammari, M., Panova-Elektronova, N. I., White, M. A., Zhou, J., & Laezza, F. (2018). Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. ACS Chemical Neuroscience, 9(5), 976-987. https://doi.org/10.1021/acschemneuro.7b00399