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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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

Fingerprint

Voltage-Gated Sodium Channels
Peptidomimetics
Modulation
Proteins
Nucleus Accumbens
Protein Transport
Drug Discovery
Modulators
Neurons
fibroblast growth factor 14
Current density
Derivatives
Kinetics
Electric potential

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

Cite this

Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. / 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; Zhou, Jia; Laezza, Fernanda.

In: ACS Chemical Neuroscience, Vol. 9, No. 5, 16.05.2018, p. 976-987.

Research output: Contribution to journalArticle

Ali, SR, Liu, Z, Nenov, MN, Folorunso, O, Singh, A, Scala, F, Chen, H, James, TF, Alshammari, M, Panova-Elektronova, NI, White, M, Zhou, J & Laezza, F 2018, 'Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic', ACS Chemical Neuroscience, vol. 9, no. 5, pp. 976-987. https://doi.org/10.1021/acschemneuro.7b00399
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 ; Zhou, Jia ; Laezza, Fernanda. / Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. In: ACS Chemical Neuroscience. 2018 ; Vol. 9, No. 5. pp. 976-987.
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