Voltage-gated Na+ channels (Nav) are the molecular determinants of action potential initiation and propagation because of their role in mediating ionic flow. Out of 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). Although the α-subunit can sufficiently confer transient Na+ currents (INa), in vivo these channels exist alongside β-subunits and are modulated by auxiliary proteins like intracellular fibroblast growth factor 14 (FGF14) through protein:protein interactions (PPI). Previous studies have identified ZL0177, a peptidomimetic derived from a short peptide sequence thought to mediate the FGF14:Nav1.6 PPI, as a functionally active modulator of Nav1.6 mediated INa. In this report, ZL0177 was chosen for selectivity studies against the α-subunit of Nav1.2 and Nav1.6 for further evaluation. Using whole-cell voltage-clamp electrophysiology, we assessed ZL0177 in cells stably expressing the α-subunit of either Nav1.2 or Nav1.6. In addition, we complemented our experimental findings with in silico docking and computational neuronal models. To that end, our findings indicate that ZL0177 modulates Nav1.2 and Nav1.6 in an isoform specific manner such that computationally derived action potentials are phenotypically divergent. Currently, peptidomimetics are not considered a gold standard of care for any CNS disorder, which supports the imperative to study these interactions. Regarding future studies, ZL0177 might prove useful as a probe in understanding developmental mechanisms or as a therapeutic advancement.
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Currents: I Sodium
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Simulation Environment: NEURON
References:
Arman P et al. (2025). FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function. Life (Basel, Switzerland). 15 [PubMed]