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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function

by
Parsa Arman
1,
Zahra Haghighijoo
1,
Carmen A. Lupascu
2,
Aditya K. Singh
1,
Nana A. Goode
1,
Timothy J. Baumgartner
1,
Jully Singh
1,
Yu Xue
1,
Pingyuan Wang
1,
Haiying Chen
1,
Dinler A. Antunes
3,
Marijn Lijffijt
4,
Jia Zhou
1,
Michele Migliore
2 and
Fernanda Laezza
1,4,*
1
Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
2
Institute of Biophysics, National Research Council, 90146 Palermo, Italy
3
Department of Biology and Biochemistry, University of Houston, Houston, TX 77004, USA
4
IonTX Inc., Friendswood, TX 77546, USA
*
Author to whom correspondence should be addressed.
Life 2025, 15(9), 1345; https://doi.org/10.3390/life15091345 (registering DOI)
Submission received: 25 June 2025 / Revised: 31 July 2025 / Accepted: 18 August 2025 / Published: 25 August 2025
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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Abstract

Voltage-gated Na+ channels (Nav) are the molecular determinants of action potential initiation and propagation. Among the nine voltage-gated Na+ channel isoforms (Nav1.1–Nav1.9), Nav1.2 and Nav1.6 are of particular interest because of their developmental expression profile throughout the central nervous system (CNS) and their association with channelopathies. Although the α-subunit coded by each of the nine isoforms can sufficiently confer transient Na+ currents (INa), in vivo these channels are modulated by auxiliary proteins like intracellular fibroblast growth factor (iFGFs) through protein–protein interaction (PPI), and probes developed from iFGF/Nav PPI complexes have been shown to precisely modulate Nav channels. Previous studies identified ZL0177, a peptidomimetic derived from a short peptide sequence at the FGF14/Nav1.6 PPI interface, as a functional modulator of Nav1.6-mediated INa+. However, the isoform specificity, binding sites, and putative physiological impact of ZL0177 on neuronal excitability remain unexplored. Here, we used automated planar patch-clamp electrophysiology to assess ZL0177’s functional activity in cells stably expressing Nav1.2 or Nav1.6. While ZL0177 was found to suppress INa in both Nav1.2- and Nav1.6-expressing cells, ZL0177 elicited functionally divergent effects on channel kinetics that were isoform-specific and supported by differential docking of the compound to AlphaFold structures of the two channel isoforms. Computational modeling predicts that ZL0177 modulates Nav1.2 and Nav1.6 in an isoform-specific manner, eliciting phenotypically divergent effects on action potential discharge. Taken together, these results highlight the potential of PPI derivatives for isoform-specific regulation of Nav channels and the development of therapeutics for channelopathies.
Keywords: voltage-gated Na+ channel (Nav); automated planar patch electrophysiology; protein–protein interaction (PPI); FGF14; Nav1.6; Nav1.2; drug discovery; central nervous system (CNS) voltage-gated Na+ channel (Nav); automated planar patch electrophysiology; protein–protein interaction (PPI); FGF14; Nav1.6; Nav1.2; drug discovery; central nervous system (CNS)
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MDPI and ACS Style

Arman, P.; Haghighijoo, Z.; Lupascu, C.A.; Singh, A.K.; Goode, N.A.; Baumgartner, T.J.; Singh, J.; Xue, Y.; Wang, P.; Chen, H.; et al. FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function. Life 2025, 15, 1345. https://doi.org/10.3390/life15091345

AMA Style

Arman P, Haghighijoo Z, Lupascu CA, Singh AK, Goode NA, Baumgartner TJ, Singh J, Xue Y, Wang P, Chen H, et al. FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function. Life. 2025; 15(9):1345. https://doi.org/10.3390/life15091345

Chicago/Turabian Style

Arman, Parsa, Zahra Haghighijoo, Carmen A. Lupascu, Aditya K. Singh, Nana A. Goode, Timothy J. Baumgartner, Jully Singh, Yu Xue, Pingyuan Wang, Haiying Chen, and et al. 2025. "FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function" Life 15, no. 9: 1345. https://doi.org/10.3390/life15091345

APA Style

Arman, P., Haghighijoo, Z., Lupascu, C. A., Singh, A. K., Goode, N. A., Baumgartner, T. J., Singh, J., Xue, Y., Wang, P., Chen, H., Antunes, D. A., Lijffijt, M., Zhou, J., Migliore, M., & Laezza, F. (2025). FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function. Life, 15(9), 1345. https://doi.org/10.3390/life15091345

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