Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na + Channel 1.6 Enables Isoform-Selective Modulation.

Voltage-gated Na + (Na v ) channels are the primary molecular determinant of the action potential. Among the nine isoforms of the Na v channel α subunit that have been described (Na v 1.1-Na v 1.9), Na v 1.1, Na v 1.2, and Na v 1.6 are the primary isoforms expressed in the central nervous system (CNS). Crucially, these three CNS Na v channel isoforms display differential expression across neuronal cell types and diverge with respect to their subcellular distributions. Considering these differences in terms of their localization, the CNS Na v channel isoforms could represent promising targets for the development of targeted neuromodulators. However, current therapeutics that target Na v channels lack selectivity, which results in deleterious side effects due to modulation of off-target Na v channel isoforms. Among the structural components of the Na v channel α subunit that could be pharmacologically targeted to achieve isoform selectivity, the C-terminal domains (CTD) of Na v channels represent promising candidates on account of displaying appreciable amino acid sequence divergence that enables functionally unique protein-protein interactions (PPIs) with Na v channel auxiliary proteins. In medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a critical brain region of the mesocorticolimbic circuit, the PPI between the CTD of the Na v 1.6 channel and its auxiliary protein fibroblast growth factor 14 (FGF14) is central to the generation of electrical outputs, underscoring its potential value as a site for targeted neuromodulation. Focusing on this PPI, we previously developed a peptidomimetic derived from residues of FGF14 that have an interaction site on the CTD of the Na v 1.6 channel. In this work, we show that whereas the compound displays dose-dependent effects on the activity of Na v 1.6 channels in heterologous cells, the compound does not affect Na v 1.1 or Na v 1.2 channels at comparable concentrations. In addition, we show that the compound correspondingly modulates the action potential discharge and the transient Na+ of MSNs of the NAc. Overall, these results demonstrate that pharmacologically targeting the FGF14 interaction site on the CTD of the Na v 1.6 channel is a strategy to achieve isoform-selective modulation, and, more broadly, that sites on the CTDs of Na v channels interacted with by auxiliary proteins could represent candidates for the development of targeted therapeutics.