Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons

Abstract

Fibroblast Growth Factor Homologous Factors (FHFs) are cytosolic members of the of the FGF proteins. Four members of this subfamily (FHF1-4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders. FHF proteins bind to the C-terminus of voltage-gated sodium (Nav) channels and regulate current amplitude and gating properties of these channels. FHF2, which is expressed in DRG neurons, has two main splicing isoforms, FHF2A and FHF2B, which differ in the length and sequence of their N-termini, have been shown to differentially regulate gating properties of Nav1.7, a channel that is a major driver of DRG neuron firing. FHF2 expression levels are downregulated following peripheral nerve axotomy, which suggests that they may regulate neuronal excitability via an action on Nav channels after injury. We have previously shown that knockdown of FHF2 leads to gain-of-function changes in Nav1.7 gating properties: enhanced repriming, increased current density and hyperpolarized activation. From this we posited that knockdown of FHF2 might also lead to DRG hyperexcitability. Here we show that knockdown of either FHF2A alone or all isoforms of FHF2 results in increased DRG neuron excitability. In addition, we demonstrate that supplementation of FHF2A and FHF2B reduces DRG neuron excitability. Overexpression of FHF2A or FHF2B also reduced excitability of DRG neurons treated with a cocktail of inflammatory mediators, a model of inflammatory pain. Our data suggest that increased neuronal excitability after nerve injury might be triggered, in part, via a loss of FHF2-Nav1.7 interaction.

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

“… 77 Inhibitory effects of intracellular FGF13A on Nav channels were reported previously. 60 , 67 , 78 , 79 , 80 , 81 However, these studies used either FGF13A transfection or very high (1 mM) intracellular concentrations of FGF13, 60 , 67 while at the more physiological (nM) concentrations used in our study, no effect was detectable following intracellular addition of FGF13A, except a mild reduction of sodium current intensities and AP amplitude. FGF13A thus appears to act mostly extracellularly to decrease neuronal excitability, while other isoforms of FGF13 or its core domain could act intracellularly.…”

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14)Increasesthe Excitability of Mature Hippocampal and Cortical Pyramidal Neurons

“…Also referred to as fibroblast growth factor homologous factors, FHF1-4, the iFGFs share sequence and structural homology with the canonical FGFs, but lack the signal sequence for secretion (Smallwood et al, 1996; Hartung et al, 1997; Munoz-Sanjuan et al, 2000; Olsen et al, 2003; Goldfarb, 2005; Pablo and Pitt, 2016; Ornitz and Itoh, 2022). The iFGFs have been shown to bind to the carboxy termini of voltage-gated Na + (Nav) channel pore-forming (α) subunits (Liu et al, 2001, 2003; Wittmack et al, 2004; Lou et al, 2005; Goetz et al, 2009; Wang et al, 2015), and to modulate the time- and voltage-dependent properties of heterologously expressed Nav channels (Liu et al, 2001, 2003; Wittmack et al, 2004; Lou et al, 2005; Rush et al, 2006; Laezza et al, 2007, 2009; Dover et al, 2010; Wang et al, 2011a), as well as of native Nav currents in cardiac (Wang et al, 2011b; Park et al, 2016; Wang et al, 2017; Abrams et al, 2020; Chakouri et al, 2022; Angsutaraux et al, 2023; Fischer et al, 2024) and neuronal (Goldfarb et al, 2007; Dover et al, 2010; Venkatesan et al, 2014; Yan et al, 2014; Bosch et al, 2015; Puranam et al, 2015; Alshammari et al, 2016; Yang et al, 2017; Effraim et al, 2019, 2022) cells.…”