Localization of the type VI voltage-gated sodium channel protein in human CNS

Whitaker, William R. J.; Faull, Richard L.M.; Waldvogel, Henry J.; Plumpton, Christopher; Burbidge, Stephen A.; Emson, Piers C.; Clare, Jeffrey J.

doi:10.1097/00001756-199911260-00044

Cited by 16 publications

(8 citation statements)

References 11 publications

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“…SCN2A distribution is somewhat complementary to SCN1A, with a rostrocaudal gradient distribution in the brain, and high expression in the cortex, hippocampus, striatum, and midbrain (Whitaker et al., 2001). SCN8A is more uniformly distributed, with high expression in the hippocampus, cortex, and cerebellum (Whitaker et al., 1999; Kress et al., 2010). In addition there are different excitability thresholds for different neurons, probably determined by differing distribution and expression of sodium channel subunits at the AIS.…”

Section: Neurobiologymentioning

confidence: 99%

Sodium channels and the neurobiology of epilepsy

2012

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SUMMARYVoltage-gated sodium channels (VGSCs) are integral membrane proteins. They are essential for normal neurologic function and are, currently, the most common recognized cause of genetic epilepsy. This review summarizes the neurobiology of VGSCs, their association with different epilepsy syndromes, and the ways in which we can experimentally interrogate their function. The most important sodium channel subunit of relevance to epilepsy is SCN1A, in which over 650 genetic variants have been discovered. SCN1A mutations are associated with a variety of epilepsy syndromes; the more severe syndromes are associated with truncation or complete loss of function of the protein. SCN2A is another important subtype associated with epilepsy syndromes, across a range of severe and less severe epilepsies. This subtype is localized primarily to excitatory neurons, and mutations have a range of functional effects on the channel. SCN8A is the other main adult subtype found in the brain and has recently emerged as an epilepsy gene, with the first human mutation discovered in a severe epilepsy syndrome. Mutations in the accessory b subunits, thought to modulate trafficking and function of the a subunits, have also been associated with epilepsy. Genome sequencing is continuing to become more affordable, and as such, the amount of incoming genetic data is continuing to increase. Current experimental approaches have struggled to keep pace with functional analysis of these mutations, and it has proved difficult to build associations between disease severity and the precise effect on channel function. These mutations have been interrogated with a range of experimental approaches, from in vitro, in vivo, to in silico. In vitro techniques will prove useful to scan mutations on a larger scale, particularly with the advance of high-throughput automated patch-clamp techniques. In vivo models enable investigation of mutation in the context of whole brains with connected networks and more closely model the human condition. In silico models can help us incorporate the impact of multiple genetic factors and investigate epistatic interactions and beyond.

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Section: Neurobiologymentioning

confidence: 99%

Sodium channels and the neurobiology of epilepsy

2012

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“…Na V 1.6 has a relatively uniform brain distribution, with high levels of expression in hippocampus, cortex and cerebellum [4, 5]. It is localised to both excitatory and inhibitory neurons [6–11].…”

Section: Introductionmentioning

confidence: 99%

Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy

Oliva

McGarr

Beyer

et al. 2014

Neurobiology of Disease

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In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8aV929F). Here, we confirmed the prior suggestion that Scn8aV929F exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8aV929F is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2V752F as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2V752F functional analysis revealed an overall gain-of-function and for NaV1.6V929F revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2V752F due to “functional silencing” of NaV1.6V929F suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6V929F loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.

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“…Na V 1.8, and Na V 1.9 are TTX-resistant (TTX-R), and the remaining α subunits are TTX-sensitive (TTX-S) [10]. Subtype localization varies: Na V 1.1, Na V 1.2, and Na V 1.3 are principally found in the central nervous system, whereas Na V 1.6, Na V 1.7, Na V 1.8, and Na V 1.9 are mostly distributed in the peripheral nervous system [10,11,12,13,14,15,16,17,18,19]. Na V 1.4 can be found in skeletal muscle, and Na V 1.5 is present predominantly in cardiac muscle [20,21].…”

Section: Introductionmentioning

confidence: 99%

Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a) Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

Luo¹,

Zhang²,

Gong³

et al. 2014

Toxins

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Voltage-gated sodium channels (VGSCs; NaV1.1–NaV1.9) have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX)-V (also known as β-theraphotoxin-Cj2a) is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK) motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7–2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7) and two cationic (R20 and K22) residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.

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Localization of the type VI voltage-gated sodium channel protein in human CNS

Cited by 16 publications

References 11 publications

Sodium channels and the neurobiology of epilepsy

Sodium channels and the neurobiology of epilepsy

Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy

Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a) Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

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