Alternative approaches, such as targeting intrinsic modulators of Nav1.7 currents in nociceptive neurons, have recently been investigated in the hopes of developing Nav1.7 inhibitors with fewer side effects (9). An intriguing study using a transgenic mouse with an epitope-tagged Nav1.7 indicated that as many as 267 proteins are associated with Nav1.7 in vivo (10). In this issue of the JCI, Singh, Bernabucci, and authors targeted a well-documented Nav1.7 interactor, FGF13, with promising results (11).

FGF13 belongs to a group of proteins produced by a subset of genes in the fibroblast growth factor family, FGF11 through FGF14. These factors have emerged as major modulators of VGSCs (12). The proteins are also known as fibroblast growth factor homologous factors (FHF1 through FHF4) because, unlike other FGFs, they do not bind FGF receptors and are not secreted like classic FGFs. The FHF terminology is generally used to distinguish these intracellular proteins from the classic FGFs. A sequence of approximately 125 amino acids at the core of these FHFs adopts a β-trefoil structure similar to that of true FGFs but with only about 30% sequence identity (13). FHF core regions have been shown to bind to the c-terminus of VGSCs, just upstream of where calmodulin binds to VGSCs (14). Intriguingly, there are multiple FHF isoforms, with each FHF gene generating at least one short isoform, often termed the “B” isoform (referred to as FGF13 in Singh et al.), and at least one isoform with a long N-terminal extension, referred to as the “A” isoform (named FGF13S in Singh et al.). FHFs are highly expressed in neurons and cardiac myocytes but can also be found in some nonexcitable tissues (12). Notably, they bind to and modulate the properties of all the VGSCs, except for perhaps Nav1.4, and are capable of modifying VGSC properties in complex ways. The most common impact of the binding of the FHF core to VGSCs is a depolarizing shift in the voltage dependence of inactivation and an enhancement of current density, both proexcitation effects. By contrast, A-type FHFs often induce a process known as long-term inactivation, where the channels appear to undergo normal fast inactivation but take much longer to recover than with typical, intrinsic VGSC fast inactivation (15). This long-term inactivation reduces action potential firing. Singh, Bernabucci, and authors focused on the B isoform of FGF13 (aka FHF2B) (11).

Genetic and preclinical studies have established FHFs as important physiological modulators of VGSCs (12). Point mutations in FGF12 and FGF13 (aka FHF1 and FHF2) cause epilepsy and intellectual disability (16, 17). Loss-of-function mutations in FHF14 are associated with spinocerebellar ataxia type 27 (18). While it is clear from these studies that FHFs contribute to epilepsy and ataxia, the role of FHFs in pain has been less clear. However, recently it was shown that FGF13 may be critical for heat nociception (19). Singh, Bernabucci, and authors (11) provide strong evidence that FGF13 can act as a pain rheostat in nociceptor neurons through its interactions with Nav1.7.

Singh, Bernabucci, and colleagues used multiple techniques to determine how the FGF13 interaction with Nav1.7 modulates current properties, neuronal excitability, and pain sensations (11). Using protein-protein interaction assays, they identified a molecule with drug-like properties, PW164, that bound at the FGF13-Nav1.7 interface. PW164 inhibited FGF13 binding to Nav1.7 and blocked the ability of FGF13 to upregulate Nav1.7 current density (Figure 1). It also blocked capsaicin-induced sodium current in human induced pluripotent stem cell–derived sensory neurons without affecting baseline currents. This finding suggests a role for the FGF13-Nav1.7 complex in hypersensitivity following exposure to noxious stimuli. Indeed, in a mouse model where hypersensitivity was induced by paw injection of capsaicin, PW164 inhibited the capsaicin-induced thermal and mechanical hypersensitivity but not baseline thermal and mechanical responses. A compound that maintains baseline nociception provides an advantage, as normal pain is an important survival mechanism. To explore the role of the FGF13-Nav1.7 interaction in a more clinically relevant pain model, the authors tested PW164 in a mouse model of type-2 diabetic neuropathy (T2DN). Mechanical hypersensitivity was substantially reduced for several hours by injection of PW164, indicating that PW164-like compounds may be efficacious against at least some forms of clinically problematic pain. Additional screens also identified the small molecule ZL192 that (a) stabilized the FGF13-Nav1.7 interaction, (b) potentiated Nav1.7 currents when FGF13 was also present, and (c) induced robust mechanical hyperalgesia and thermal hypersensitivity in mice. This result further validated the importance of the FGF13-Nav1.7 interaction in regulating pain sensitivity.

PW164 inhibits pain hypersensitivity. (A) Nav1.7 channels are expressed in nociceptor neurons along with FGF13 (FHF2B), Nav1.8, and the capsaicin receptor TrpV1. (B) Noxious stimuli and painful conditions enhance Nav1.7 surface expression and pain hypersensitivity by increasing the interaction between FGF13 and Nav1.7. (C) PW164 binding to FGF13 prevents the increase in Nav1.7 currents, inhibiting nociceptor activity and reducing pain.