A Functional Null Mutation of<i>SCN1B</i>in a Patient with Dravet Syndrome

Patino, Gustavo; Claes, Lieve; Lopez-Santiago, Luis F.; Slat, Emily A.; Dondeti, Raja S.R.; Chen, Chunling; O’Malley, Heather A.; Gray, Charles B.B.; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; Jonghe, Peter De; Isom, Lori L.

doi:10.1523/jneurosci.2475-09.2009

Cited by 226 publications

(282 citation statements)

References 72 publications

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“…Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12,13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14)(15)(16)(17)(18)(19)(20)(21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactions in vitro (11).…”

mentioning

confidence: 71%

“…Given that Scn1b mutations result in channelopathies in vivo (12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and that β1-mediated neurite outgrowth in CGNs requires I Na and Na v 1.6, we postulated that β1 might regulate electrical excitability in the cerebellum. To test this, we recorded APs in P12-13 WT and Scn1b null CGNs in cerebellar slices by whole-cell patch clamping.…”

Section: Resultsmentioning

confidence: 99%

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Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

159

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Voltage-gated Na + channel (VGSC) β1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na + current (I Na ) mediated by Na v 1.6. In addition, β1 is required for highfrequency action potential firing. Transient I Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I Na , thought to underlie high-frequency firing in Na v 1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na v 1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v 1.6 at the AIS, we observed an increase in Na v 1.1, whereas Na v 1.2 was unchanged. This indicates that β1 is required for normal localization of Na v 1.6 at the AIS during the postnatal developmental switch to Na v 1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na v 1.6 such that β1-mediated neurite outgrowth requires Na v 1.6-mediated I Na , and Na v 1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.V oltage-gated Na + channels (VGSCs), composed of one poreforming α subunit and two β subunits (1), are responsible for initiation and conduction of action potentials (APs) (2). Of the nine α subunits (3), Na v 1.1, Na v 1.2, and Na v 1.6 are found in the postnatal CNS (4, 5) where they display developmentally regulated expression patterns in specialized neuronal subcellular domains. For example, Na v 1.1 and Na v 1.2 are replaced during postnatal development at the axon initial segment (AIS) and nodes of Ranvier by Na v 1.6. Scn8a null mice display motor dysfunction, ataxia, and lethality by postnatal day (P) 21, suggesting that this developmental switch to Na v 1.6 expression in brain is critical (6, 7). Scn8a null retinal ganglion neurons display impaired excitability, demonstrating that Na v 1.6 is vital for high-frequency firing (8-10). Thus, VGSC-driven neuronal activity is important for proper CNS development, although the underlying mechanism(s) are not well understood.VGSC β1 subunits are multifunctional molecules that modulate channel kinetics and gating, regulate channel cell surface expression, and participate in cell-cell adhesion in vitro (11). Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12, 13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14-21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactio...

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mentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

159

View full text Add to dashboard Cite

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“…Importantly, our data may be translated to imply that human patients with inherited SCN1B-mediated GEFS ϩ epilepsies (34), especially patients with two inherited functional null SCN1B mutant alleles resulting in Dravet syndrome (35), may have increased sensitivity to pain.…”

Section: Discussionmentioning

confidence: 93%

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

Lopez-Santiago

Brackenbury²,

Chen

et al. 2011

Journal of Biological Chemistry

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Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na ؉ current (I Na ) mediated by voltage-gated Na ؉ channels (VGSCs). In nociceptive DRG neurons, VGSC ␤2 subunits, encoded by Scn2b, selectively regulate TTX-S ␣ subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by ␤1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S I Na inactivation, reduced persistent TTX-R I Na , a prolonged rate of recovery of TTX-R I Na from inactivation, and reduced cell surface expression of Na v 1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K ؉ current (I to ) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both I Na and I K .VGSCs 3 comprise one pore-forming ␣ subunit and two ␤ subunits (␤1-␤4, encoded by Scn1b-Scn4b) that do not form the pore but play critical roles in channel subcellular localization, regulation of I Na , VGSC gene transcription, and cell adhesive interactions leading to cytoskeletal modulation, changes in cell morphology, and cellular migration (1-3).All four mammalian VGSC ␤ subunit gene products are expressed in DRG neurons (4); however, little is known about their roles in nociception. The role of Scn1b in DRG neurons in vivo has not been investigated. Scn1b mRNA is expressed in DRG neurons (4), and the Scn1b splice variant ␤1B is expressed in adult rat DRG neurons as assessed by immunohistochemistry (5). Scn1b mRNA expression changes in the dorsal horn of the spinal cord in a model of neuropathic pain in rats (6), suggesting that ␤1/␤1B are important in nociception. Despite this, the effects of ␤1 on the functioning of heterologously overexpressed sensory neuronal VGSCs are controversial.

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“…To test the possibility that eukaryotic β-subunits may also modulate bNa V s, cRNA encoding NaChBac was co-injected with eukaryotic Na V β1 and β2 in Xenopus laevis oocytes, an expression system that lacks endogenous β-subunit expression, unlike a majority of mammalian cell lines (3,(81)(82)(83)(84)(85). Coexpression of NaChBac with β1 in Xenopus oocytes significantly increased sodium current amplitudes over NaChBac alone and this trend was sustained over a 50-hour time course (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel

Molinarolo

Lee

Leisle

et al. 2018

Journal of Biological Chemistry

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Voltage-gated, sodium ion-selective channels (Na V ) generate electrical signals contributing to the upstroke of the action potential in animals. Na V s are also found in bacteria and are members of a larger family of tetrameric voltagegated channels that includes Ca V s, K V s, and Na V s. Prokaryotic Na V s likely emerged from a homotetrameric Ca 2+ -selective voltage-gated progenerator, and later developed Na + selectivity independently. The Na V signaling complex in eukaryotes contains auxiliary proteins, termed beta (β) subunits, which are potent modulators of the expression profiles and voltage-gated properties of the Na V pore, but it is unknown whether they can functionally interact with prokaryotic Na V channels. Herein, we report that the eukaryotic Na V β1-subunit isoform interacts with and enhances the surface expression as well as the voltage-dependent gating properties of the bacterial Na V , NaChBac in Xenopus oocytes. A phylogenetic analysis of the β-subunit gene family proteins confirms that these proteins appeared roughly 420 million years ago and that they have no clear homologues in bacterial phyla. However, a comparison between eukaryotic and bacterial Na V structures highlighted the presence of a conserved fold, which could support interactions with the β-subunit. Our the electrophysiological, biochemical, structural and bioinformatics results suggests that the prerequisites for β-subunit regulation are an evolutionarily stable and intrinsic property of some voltage-gated channels.

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A Functional Null Mutation ofSCN1Bin a Patient with Dravet Syndrome

Cited by 226 publications

References 72 publications

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel

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A Functional Null Mutation ofSCN1Bin a Patient with Dravet Syndrome

Cited by 226 publications

References 72 publications

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel

Contact Info

Product

Resources

About

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth