Angsutararux P , Dutta AK , Marras M , Abella C , Mellor RL , Shi J , Nerbonne JM , Silva JR .

P30 NS057105 NINDS NIH HHS , UL1 RR024992 NCRR NIH HHS , UL1 TR002345 NCATS NIH HHS , NHLBI NIH HHS , R01 142520 NIH HHS , R01 HL150637 NHLBI NIH HHS , R01 HL142520 NHLBI NIH HHS

	Figure S1. Targeted disruption of the Fgf13 locus and generation/validation of cardiac-specific Fgf13 targeted deletion mice. (A) Schematics of the endogenous Fgf13 locus (top), located on the X chromosome, and the floxed Fgf13 locus (middle). Following sequencing of the first and second generation of offspring, heterozygous Fgf13 floxed (Fgf13fl/+) female mice and hemizygous Fgf13 floxed (Fgf13fl/y) male mice were crossed to also generate homozygous Fgf13 floxed (Fgf13fl/fl) females. The Fgf13fl/y and Fgf13fl/fl animals were then crossed with transgenic mice expressing Cre recombinase driven by the cardiac-specific α-MHC promoter. Crossing the Cre recombinase positive, hemizygous floxed male (Fgf13fl/y) offspring with Fgf13fl/fl females (or Cre recombinase heterozygous Fgf13fl/+ females with Fgf13fl/y males) provided cardiac-specific Fgf13 targeted deletion hemizygous male and homozygous female animals, referred to collectively here as cardiac-specific Fgf13 knockouts, cFgf13KO. Three sets of primers were employed to detect the 5′ LoxP site, the 3′ LoxP site, and the α-MHC-driven Cre-recombinase (see Materials and methods). (B) Representative results from PCR analyses of homozygous Fgf13fl/fl, heterozygous Fgf13fl/+, and WT (+/+) female mice using primers targeting the 5′ LoxP site (left) and the 3′ LoxP site (middle) are shown. Further screening of these animals with primers to the α-MHC–Cre-recombinase transgene identified Cre recombinase positive animals (right). (C) Western blot analyses confirmed loss of iFGF13 protein expression. Protein lysates (1 µg), prepared from WT, cFgf13KO, and Fgf12 targeted deletion (Fgf12KO) ventricles, were fractionated, transferred, and membranes were probed with an anti-iFGF13 antibody, as described in Materials and methods. A prominent band at ∼32 kD and a faint band at ∼24 kD were detected with the anti-iFGF13 antibody in the WT (left and right panels) and Fgf12KO (right panel) LV protein samples, whereas these bands were not detected in the cFgf13KO LV samples (left panel), consistent with the elimination of iFGF13 proteins. Source data are available for this figure: SourceData FS1.
	Figure S2. Loss of Fgf13 or Fgf12 does not measurably affect the expression levels of other Fgf transcripts in adult mouse LV. The expression levels of the Fgf11, Fgf12A, Fgf12B, Fgf13S(A), Fgf13VY, Fgf13U(B), Fgf14A, and Fgf14B transcripts in WT, cFgf13KO, and Fgf12KO LV samples were measured and normalized to Hprt expression in the same sample, as described in Materials and methods. These analyses revealed that the Fgf13 transcripts are undetectable in cFgf13KO LV. In addition, the mean ± SEM relative expression levels of the other Fgf transcripts in cFgf13KO and WT LV are indistinguishable.
	Figure 1. Cardiac-specific deletion of Fgf13 (cFgf13KO) alters inactivation, but not activation, of INa in LV myocytes. (A) Representative INa waveforms recorded from LV myocytes isolated from WT (black) and cardiac-specific Fgf13 deletion (cFgf13KO; orange) mice; the voltage-clamp protocol is illustrated below the current records. (B) Mean ± SEM normalized conductances (G) of INa activation and inactivation were plotted as a function of voltage and fitted to single Boltzmann functions (solid lines). There is a marked hyperpolarizing shift in the voltage-dependence of INa inactivation in cFgf13KO (orange) compared with WT (black) LV myocytes (P value <0.001; Table 1), whereas the voltage-dependences of INa activation are indistinguishable in cFgf13KO and WT LV myocytes (P value = 0.12; Table 1). Control experiments revealed that the voltage-dependences of INa activation and inactivation in Fgf13 floxed (grey) LV myocytes are indistinguishable from WT LV myocytes (P values are 0.11 and 0.97, respectively; Table 1). It was not possible, however, to conduct additional control experiments to independently determine if there are any of the previously reported cardiotoxic effects (Pugach et al., 2015) of the prolonged expression of Cre-recombinase in our cFgf13KO mice. (C) Analysis of INa recovery from inactivation, examined using a three-step protocol as described in Materials and methods, reveals that recovery follows a biexponential time course (see Table 1). The decay phases of INa in all WT adult mouse LV myocytes were best fitted with the sum of two exponentials as described in Materials and methods. (D) The mean ± SEM (n = 19) fast (Ƭf) and slow (Ƭs) time constants of INa decay determined in WT cells are plotted as a function of the test potentials in D. As is evident, neither time constant displays any appreciable voltage dependence (P value = 0.26; Table 1). Inset: Overlaying representative INa waveforms recorded from cFgf13KO and WT LV myocytes reveal that current decay is accelerated in cFgf13KO compared with WT cells. Indeed, in 13 (of 26) cFgf13KO LV myocytes, the decay phases of INa were best described by single exponentials characterized (see text near Fig. 1 D citation) by Ƭ values indistinguishable from Ƭf determined in WT cells, i.e., the slow component of INa decay was undetectable in these 13 cells. For the remaining 13 (of 26) cFgf13KO LV myocytes, INa decay was well described by two exponentials, with Ƭf and Ƭs values similar to those determined in WT cells at all test potentials (see values in Table S2). (E) The mean ± SEM fractional amplitudes of the slow component of INa decay (%Aslow) in these (13 of 26) cFgf13KO LV myocytes, however, were significantly lower than those determined in WT cells at all test potentials (see values in Table S2).
	Figure S3. The amplitudes/densities of INa in mouse LV myocytes are not affected by the loss of iFGF13, and the properties of INa in mouse LV myocytes are not affected by the loss of iFGF12. (A) The cardiac-specific deletion of Fgf13 does not affect peak INa densities in LV myocytes: peak INa densities at all voltages in WT, Fgf13 floxed, and cFgf13KO mouse LV myocytes are not significantly different (P values >0.15 at all voltages). (B and C) Consistent with the negligible expression of Fgf12 transcripts in adult mouse LV (see Fig. S2), peak INa densities at all voltages (B) and the voltage-dependences of INa activation and inactivation (C) determined in adult Fgf12KO LV myocytes are indistinguishable (P values >0.13) from INa in WT LV myocytes at all voltages.
	Figure S4. The time-dependence of AAV9-mediated expression of iFGF12B and eGFP in adult mouse LV and the validation of the anti-iFGF12 antibody. (A and B) Western blots of fractionated protein lysates prepared from cFgf13KO ventricles 2, 3, or 4 wk following retro-orbital injections of a 1:1 mixture of the hFGF12B-expressing and eGFP-expressing AAV9 viruses, probed with an anti-EGFP (A) or anti-iFGF12 (B) antibody, as described in Materials and methods. (C) To validate the anti-iFGF12 antibody used in the Western blot in B, protein lysates prepared from WT and Fgf12KO adult mouse left and right atria were fractionated, transferred, and the membranes were probed with an anti-iFGF12 antibody, as described in Materials and methods. A prominent band at ∼20 kD was detected with the anti-iFGF12 antibody in the WT, but not in the Fgf12KO, atrial protein samples, consistent with the elimination of iFGF12 proteins and validating the anti-iFGF12 antibody for Western blot analyses of iFGF12 protein expression. Source data are available for this figure: SourceData FS4.
	Figure 2. Expression of iFGF12B in cFgf13KO LV myocytes alters the voltage-dependence of INa activation and inactivation. (A) Representative INa waveforms recorded from cFgf13KO LV myocytes without (orange) and with (blue) iFGF12B expression; the voltage-clamp protocol is illustrated below the current records. (B) The expression of iFGF12B in cFgf13KO LV myocytes resulted in depolarizing shifts in INa activation and inactivation (blue) compared with cFgf13KO LV myocytes (orange; P values are <0.001 for both G-V activation and inactivation; Table 1). (C) Expression of iFGF12B in cFgf13KO LV myocytes also accelerated INa recovery from inactivation compared with the currents in both WT and cFgf13KO LV myocytes (P value = 0.04; Table 1). (D) The decay phases of the currents in cFgf13KO cells expressing iFGF12B (blue), however, are indistinguishable from cFgf13KO (orange) LV myocytes (inset). In addition, in 13 (of 19) cFgf13KO + iFGF12B-expressing LV myocytes, the decay phases of INa were best described by single exponentials with Ƭ values indistinguishable from Ƭf determined in WT cells, i.e., the slow component of INa decay was undetectable in these 13 cells. In the remaining (6 of 19) cFgf13KO + iFGF12B-expressing LV myocytes, INa decay was well described by the sum of two exponentials (D) with Ƭf and Ƭs values similar to those in cFgf13KO and WT (Fig. 1 D) cells (see values in Table S2). (E) In addition, the fractional amplitudes of the slow component of INa decay (%Aslow) in cFgf13KO + iFGF12B-expressing LV myocytes are indistinguishable at all test potentials from those determined in cFgf13KO cells (see values in Table S2).
	Figure 3. Coexpression of iFGF12B modulates the time- and voltage-dependent properties of NaV1.5-encoded currents in Xenopus oocytes. (A) Representative human NaV1.5-encoded (INa) waveforms recorded from Xenopus oocytes expressing NaV1.5 alone (black) or together with iFGF12B (blue); the voltage-clamp protocol is illustrated below the current records. (B) The mean ± SEM normalized conductance-versus-voltage plots reveal marked depolarizing shifts in the voltage-dependences of activation and inactivation of the currents with iFGF12B coexpression (blue), relative to NaV1.5 expressed alone (black; P values are 0.012 and <0.001, respectively; Table 2). (C) The rate of INa recovery from inactivation is also accelerated with iFGF12B coexpression (P value = 0.04; Table 2). (D and E) Inset: Overlaying representative INa waveforms, recorded on membrane depolarizations to −20 mV, illustrates the difference in the decay phases of the currents recorded from Xenopus oocytes expressing NaV1.5 alone (black) or NaV1.5 with iFGF12B (blue). Analyses of the decay phases of the currents revealed that the time constants of the fast and slow components of INa decay (Ƭf and Ƭs, respectively; D) are indistinguishable in the absence and the presence of iFGF12B, whereas the fractional amplitude of the slow component of current decay (%Aslow; E) was reduced markedly with iFGF12B coexpression at all test potentials (see values in Table S3).
	Figure 4. iFGF12B regulates the activation of the voltage sensor in repeat IV of NaV1.5. VCF recordings were obtained as described in Materials and methods. Representative fluorescence signals recorded from Xenopus oocytes expressing NaV1.5 alone (black) or with iFGF12B (blue) in response to 50-ms depolarizing voltage steps to −140, −80, −20, and 40 mV, are presented; only four fluorescence traces are shown for clarity. The mean ± SEM normalized steady-state fluorescence signals were plotted and fitted with a single Boltzmann function (solid lines). Coexpression of iFGF12B induced a hyperpolarizing shift in the VSD-IV F-V curve (P value <0.001, Table 3), but caused no change in the F-V curves of the other VSDs (see Table 3).
	Figure 5. Coexpression of iFGF13VY affects the voltage dependence of steady-state inactivation and the inactivation kinetics of NaV1.5-encoded currents in Xenopus oocytes. (A) Representative INa waveforms recorded from Xenopus oocytes expressing NaV1.5 alone (black) or with iFGF13VY (orange); the voltage-clamp protocol is illustrated below the current records. (B) The mean ± SEM conductance versus voltage plots reveal marked depolarizing shifts in the voltage dependence of inactivation with iFGF13VY coexpression compared with NaV1.5 expressed alone (P value <0.001; Table 2). The voltage dependence of INa activation, however, is not affected by iFGF13VY (P value = 0.3; Table 2). (C and D) Coexpression of iFGF13VY accelerated INa recovery from inactivation (C; P value <0.001; Table 2) and overlay of representative INa waveforms (D, inset), evoked at −20 mV, illustrates the difference in the decay phases of INa in recordings from Xenopus oocytes expressing NaV1.5 without (black) and with (orange) iFGF13VY. (E) Analyses of the decay phases of the currents revealed that the time constants, Ƭf and Ƭs, of the fast and slow components of INa decay, respectively, (D) are indistinguishable for the currents in the absence and presence of iFGF13VY, whereas the fractional amplitude of the slow component of current decay (%Aslow; E) was reduced markedly with iFGF13VY coexpression at all test potentials (see values in Table S3).
	Figure 6. Distinct modulation of NaV1.5 voltage sensor conformations with iFGF13VY coexpression. The F-V curves for all four VSDs of NaV1.5 recorded from Xenopus oocytes expressing NaV1.5 alone (black) or with iFGF13VY (orange) show that iFGF13VY affects the voltage-dependences of activation of VSD-I and VSD-IV. For VSD-I, iFGF13VY coexpression shifts the F-V curve toward depolarizing potentials (P value = 0.002; Table 3). For VSD-IV, the F-V curves show that iFGF13VY results in a steeper slope and a small shift toward more hyperpolarized membrane potentials relative to NaV1.5 expressed alone (P values are 0.022 and <0.001, respectively; Table 3). The effect on the VSD-IV F-V curve with iFGF13VY coexpression is distinct from that observed with iFGF12B coexpression (compare with Fig. 4).
	Figure 7. Analysis of iFGF12B, iFGF13VY, and iFGF12B/13VY chimeras reveals a strong correlation between the slopes of the VSD-IV F-V curves and the slow component of INa inactivation. (A) Alignment of the iFGF12B and iFGF13VY sequences highlights the prominent difference in N-termini. (B–D) Several iFGF12B/13VY chimeras were constructed by swapping the N-termini, C-termini, and both C- and N-termini domains. Each chimera was coexpressed with NaV1.5, and effects on the time-and voltage-dependent properties of INa and VSD-IV activation were determined. Correlation and linear regression analyses were performed on these results obtained from iFGF chimeras, iFGF12B, and iFGF13VY. (B and C) The analyses revealed that the slow time constants of INa decay (Ƭs; B) and the fractional amplitudes of the slow component (%Aslow; C), determined for currents evoked at 0 mV, are both strongly (negatively [B] or positively [C]) correlated with the VSD-IV F-V k values. (D) The k and V1/2 values, determined from the VSD-IV F-V curves, can be used to predict %Aslow.
	Figure S5. Switching N-terminal domains between iFGF12B and iFGF13VY is not sufficient to replicate the iFGF-specific modulation of NaV1.5 gating and function. (A) Schematics of iFGF12B, iFGF13VY, and the iFGF chimeras generated with the iFGF12B and iFGF13VY N-termini exchanged (iFGF12B/13 and iFGF13VY/12). (B) Normalized inactivation, G-V, and VSD-IV F-V curves for NaV1.5 expressed alone (grey dashed line), with iFGF12B (blue dashed line), iFGF13VY (orange dashed line), or one of the iFGF chimeras, FGF12B/13 (blue triangle) or FGF13VY/12 (orange diamond). The effects of the two iFGF chimeras on the G-V and F-V curves are distinct from those observed with either iFGF12B or iFGF13VY, implying that the N-termini of iFGF12B and iFGF13VY alone do not confer iFGF-specific regulation of NaV1.5.
	Figure S6. iFGF chimeras differentially modulate the voltage dependence of VSD-IV activation (VSD-IV F-V). Three pairs of iFGF chimeras were constructed by switching the various iFGF domains of iFGF12B and iFGF13VY: the N-termini (left), the C-termini (middle), and both the N- and C-termini (right). The VSD-IV F-V curves of the various iFGF chimeras (black circle) are plotted together with those of either iFGF12B (blue dashed line) or iFGF13VY (orange dashed line). The top row presents data for iFGF chimeras with the iFGF13VY core domain and the iFGF12B N- (left), C- (middle), or both N- and C-termini (right) exchanged, and the bottom row shows the reverse configurations, i.e., the iFGF12B core domain with the iFGF13VY N- (left), C- (middle), or both N- and C-termini (right) exchanged. In both cases, the exchanged domain(s) is (are) underlined. As is evident, none of these chimeras confer functional effects on the activation of VSD-IV identical to those seen with native iFGF12B or iFGF13VY.
	Figure S7. Correlation and linear regression analyses reveal no correlations between the VSD-IV F-V and the G-V curves of activation and inactivation determined for NaV1.5 coexpressed with iFGF12B, iFGF13VY, or the iFGF12B/13VY chimeras. The data derived from the voltage-clamp and VCF recordings of NaV1.5 coexpressed with iFGF12B, iFGF13VY, and the iFGF12B/13VY chimeras were plotted to determine if there were any correlations between the parameters (V1/2 and k) derived from the Boltzmann fits to the VSD-IV F-V and the G-V curves. (A and B) As is evident in the plots shown, there are no correlations between V1/2 determined from the VSD-IV F-V curves and the G-V curves for INa inactivation (A) or activation (B). (C and D) Comparison of the slope factors, k, of VSD-IV F-V and the G-V curves reveals a modest correlation for INa inactivation (C), but no correlation for INa activation (D). (E and F) In addition, the VSD-IV F-V V1/2 values are not well correlated with either the slow inactivation time constants (E) or the fractional amplitudes of the slow component of INa decay (F). (G) The k and V1/2 values, determined from the VSD-IV F-V curves, cannot be used to predict the inactivation G-V V1/2 values.
	Figure 8. The mechanism of iFGF regulation of the NaV channel gating. At the resting membrane potential, the closed-state NaV channel has all voltage sensors (VSD-I–VSD-IV) down in their resting conformations and the activation gate is closed. This schematic portrays two interactions between the resting VSD-IV and the C-terminal domain, and the C-terminal domain and the III–IV linker in the NaV channel, as proposed by Clairfeuille et al. (2019). The activation of VSD-I to VSD-III leads to the transition of NaV1.5 from a closed to an open state, allowing for Na+ conductance. The resulting activation of VSD-IV facilitates NaV channel fast inactivation. The coexpression of iFGF facilitates the activation of VSD-IV and thus facilitates the NaV1.5 channel inactivation.

Abrams, Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels. 2020, Pubmed

Abrams, Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels. 2020, Pubmed
Abriel, Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology. 2010, Pubmed
Abriel, Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. 2005, Pubmed
Ali, Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. 2018, Pubmed
Angsutararux, Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation. 2021, Pubmed
Angsutararux, Molecular Pathology of Sodium Channel Beta-Subunit Variants. 2021, Pubmed
Barbosa, FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. 2017, Pubmed
Brunet, Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles. 2004, Pubmed
Burel, C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. 2017, Pubmed
Calhoun, The role of non-pore-forming β subunits in physiology and pathophysiology of voltage-gated sodium channels. 2014, Pubmed
Campos, Effects of bound ts3 on voltage dependence of sodium channel transitions to and from inactivation and energetics of its unbinding. 2006, Pubmed
Campos, Voltage-dependent displacement of the scorpion toxin Ts3 from sodium channels and its implication on the control of inactivation. 2004, Pubmed
Campos, Alpha-scorpion toxin impairs a conformational change that leads to fast inactivation of muscle sodium channels. 2008, Pubmed , Xenbase
Capes, Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels. 2013, Pubmed , Xenbase
Chahine, Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. 1994, Pubmed
Chakouri, Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current. 2022, Pubmed
Chanda, Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation. 2002, Pubmed , Xenbase
Chanda, Coupling interactions between voltage sensors of the sodium channel as revealed by site-specific measurements. 2004, Pubmed
Clairfeuille, Structural basis of α-scorpion toxin action on Nav channels. 2019, Pubmed
de Kok, Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. 2005, Pubmed
Dhar Malhotra, Characterization of sodium channel alpha- and beta-subunits in rat and mouse cardiac myocytes. 2001, Pubmed
Doudna, Genome editing. The new frontier of genome engineering with CRISPR-Cas9. 2014, Pubmed
Gabelli, Regulation of the NaV1.5 cytoplasmic domain by calmodulin. 2014, Pubmed
Gade, An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF. 2020, Pubmed
Gandhi, The voltage-clamp fluorometry technique. 2008, Pubmed , Xenbase
Gardill, Crystal structures of Ca2+-calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation. 2019, Pubmed
Goetz, Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. 2009, Pubmed
Goldfarb, Fibroblast growth factor homologous factors: evolution, structure, and function. 2005, Pubmed
Goldfarb, Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. 2007, Pubmed
Hanck, Site-3 toxins and cardiac sodium channels. 2007, Pubmed
Hennessey, FGF12 is a candidate Brugada syndrome locus. 2013, Pubmed
Horn, Immobilizing the moving parts of voltage-gated ion channels. 2000, Pubmed
Hsu, Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains. 2017, Pubmed , Xenbase
Iqbal, Phosphorylation of cardiac voltage-gated sodium channel: Potential players with multiple dimensions. 2019, Pubmed
Jiang, Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin. 2021, Pubmed
Jiang, Open-state structure and pore gating mechanism of the cardiac sodium channel. 2021, Pubmed
Laezza, FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. 2009, Pubmed
Li, De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia. 2017, Pubmed
Liu, Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B. 2003, Pubmed
Liu Cj, Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN). 2001, Pubmed
Lopez-Santiago, Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. 2007, Pubmed
Lorenzini, Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites. 2021, Pubmed
Lou, Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. 2005, Pubmed
Maier, Distinct subcellular localization of different sodium channel alpha and beta subunits in single ventricular myocytes from mouse heart. 2004, Pubmed
Mangold, Mechanisms and models of cardiac sodium channel inactivation. 2017, Pubmed
Mannuzzu, Direct physical measure of conformational rearrangement underlying potassium channel gating. 1996, Pubmed , Xenbase
Marionneau, Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K+ currents with left ventricular hypertrophy. 2008, Pubmed
Meadows, Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes. 2005, Pubmed
Munoz-Sanjuan, Isoform diversity among fibroblast growth factor homologous factors is generated by alternative promoter usage and differential splicing. 2000, Pubmed
Muroi, Local anesthetics disrupt energetic coupling between the voltage-sensing segments of a sodium channel. 2009, Pubmed , Xenbase
Musa, SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia. 2015, Pubmed
Nerbonne, Molecular physiology of cardiac repolarization. 2005, Pubmed
Noble, Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. 2006, Pubmed
Olsen, Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. 2003, Pubmed
Pablo, Fibroblast Growth Factor Homologous Factors: New Roles in Neuronal Health and Disease. 2016, Pubmed
Park, Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. 2016, Pubmed
Park, Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart. 2020, Pubmed
Pitt, Current view on regulation of voltage-gated sodium channels by calcium and auxiliary proteins. 2016, Pubmed
Pugach, Prolonged Cre expression driven by the α-myosin heavy chain promoter can be cardiotoxic. 2015, Pubmed
Ransdell, Intrinsic mechanisms in the gating of resurgent Na+ currents. 2022, Pubmed
Richmond, Slow inactivation in human cardiac sodium channels. 1998, Pubmed , Xenbase
Ruan, Sodium channel mutations and arrhythmias. 2009, Pubmed
Rudokas, The Xenopus oocyte cut-open vaseline gap voltage-clamp technique with fluorometry. 2014, Pubmed , Xenbase
Schmittgen, Analyzing real-time PCR data by the comparative C(T) method. 2008, Pubmed
Sentmanat, Highly reliable creation of floxed alleles by electroporating single-cell embryos. 2022, Pubmed
Silva, Slow inactivation of Na(+) channels. 2014, Pubmed
Silva, Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4. 2013, Pubmed , Xenbase
Silva, Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: a periodic paralysis mutation in Na(V)1.4 (L689I). 2013, Pubmed , Xenbase
Singh, Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability. 2020, Pubmed
Singh, Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14. 2021, Pubmed
Stefani, Cut-open oocyte voltage-clamp technique. 1998, Pubmed , Xenbase
Ton, Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart. 2021, Pubmed
Varga, Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations. 2015, Pubmed
Velíšková, Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain-of-function FHF1(FGF12) missense mutation. 2021, Pubmed
Wang, Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts. 2011, Pubmed
Wang, Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels. 2011, Pubmed
Wang, Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. 2012, Pubmed
Wang, Structural analyses of Ca²⁺/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation. 2014, Pubmed
Wang, Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. 2017, Pubmed
White, Effects of FGF14 and NaVβ4 deletion on transient and resurgent Na current in cerebellar Purkinje neurons. 2019, Pubmed
Xu, Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. 1999, Pubmed
Yan, FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons. 2014, Pubmed
Yang, FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner. 2016, Pubmed
Yu, Overview of the voltage-gated sodium channel family. 2003, Pubmed
Zhu, Molecular motions that shape the cardiac action potential: Insights from voltage clamp fluorometry. 2016, Pubmed
Zhu, Mechanisms of noncovalent β subunit regulation of NaV channel gating. 2017, Pubmed
Zhu, Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits. 2021, Pubmed
Zolotukhin, Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. 2002, Pubmed