Abstract
The voltage-gated Na+ (Nav) channel is a primary molecular determinant of the initiation and propagation of the action potential. Despite the central role of the pore-forming α subunit in conferring this functionality, protein:protein interactions (PPI) between the α subunit and auxiliary proteins are necessary for the full physiological activity of Nav channels. In the central nervous system (CNS), one such PPI occurs between the C-terminal domain of the Nav1.6 channel and fibroblast growth factor 14 (FGF14). Given the primacy of this PPI in regulating the excitability of neurons in clinically relevant brain regions, peptides targeting the FGF14:Nav1.6 PPI interface could be of pre-clinical value. In this work, we pharmacologically evaluated peptides derived from FGF14 that correspond to residues that are at FGF14’s PPI interface with the CTD of Nav1.6. These peptides, Pro-Leu-Glu-Val (PLEV) and Glu-Tyr-Tyr-Val (EYYV), which correspond to residues of the β12 sheet and β8-β9 loop of FGF14, respectively, were shown to inhibit FGF14:Nav1.6 complex assembly. In functional studies using whole-cell patch-clamp electrophysiology, PLEV and EYYV were shown to confer differential modulation of Nav1.6-mediated currents through mechanisms dependent upon the presence of FGF14. Crucially, these FGF14-dependent effects of PLEV and EYYV on Nav1.6-mediated currents were further shown to be dependent on the N-terminal domain of FGF14. Overall, these data suggest that the PLEV and EYYV peptides represent scaffolds to interrogate the Nav1.6 channel macromolecular complex in an effort to develop targeted pharmacological modulators.
Highlights
Voltage-gated Na+ (Nav) channels are responsible for the initiation and propagation of action potentials in excitable cells (Catterall, 2012)
Nav1.6 are expressed in the central nervous system (CNS); Nav1.4 is expressed in skeletal muscle; Nav1.5 is expressed in cardiac muscle; and Nav1.7-Nav1.9 are expressed in the peripheral nervous system (PNS) (Goldin et al, 2000; Yu and Catterall, 2003; Catterall et al, 2005; Chahine et al, 2008; SavioGalimberti et al, 2012; Dib-Hajj et al, 2015)
PLEV corresponds to an amino acid sequence on the β12 sheet of fibroblast growth factor 14 (FGF14), and EYYV corresponds to a sequence on the β8-β9 loop of FGF14 (Ali et al, 2014)
Summary
Voltage-gated Na+ (Nav) channels are responsible for the initiation and propagation of action potentials in excitable cells (Catterall, 2012). Nav1.6 are expressed in the central nervous system (CNS); Nav1.4 is expressed in skeletal muscle; Nav1.5 is expressed in cardiac muscle; and Nav1.7-Nav1.9 are expressed in the peripheral nervous system (PNS) (Goldin et al, 2000; Yu and Catterall, 2003; Catterall et al, 2005; Chahine et al, 2008; SavioGalimberti et al, 2012; Dib-Hajj et al, 2015) Given this ubiquitous expression throughout the body, it is unsurprising that mutations to specific Nav channel isoforms give rise to an array of disease-states including autism spectrum disorder (Sanders et al, 2012; Tavassoli et al, 2014), ataxia (SavioGalimberti et al, 2012), Dravet syndrome, cognitive impairment, epilepsy (Claes et al, 2001; Mantegazza et al, 2005, 2010; Catterall et al, 2010; Volkers et al, 2011; Schaefer et al, 2013; Oyrer et al, 2018), Brugada syndrome (Probst et al, 2009), pain-related syndromes (Woods et al, 2015; Wright et al, 2016), primary erythromelalgia (Tang et al, 2015), paroxysmal extreme pain disorder (Dib-Hajj et al, 2009; Lampert et al, 2010); and cardiac arrhythmias (Wang et al, 1995; Musa et al, 2015).
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