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.