Distribution of voltage-gated sodium channel ?-subunit and ?-subunit mRNAs in human hippocampal formation, cortex, and cerebellum

Whitaker, William R. J.; Clare, Jeffrey J.; Powell, Andrew J.; Chen, Yu Hua; Faull, Richard L.M.; Emson, Piers C.

doi:10.1002/(sici)1096-9861(20000619)422:1<123::aid-cne8>3.0.co;2-x

Cited by 125 publications

(82 citation statements)

References 64 publications

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“…In multiple animal models of spontaneous seizures, the voltage dependence of sodium current inactivation in hippocampal CA1 pyramidal and dentate granule neurons was shifted toward depolarized potentials, resulting in increased sodium channel availability and window current (Vreugdenhil et al, 1998;Gu et al, 2001;Ketelaars et al, 2001;Ellerkmann et al, 2003). Na v 1.1 is known to be expressed in the adult hippocampus and dentate gyrus and could therefore play a critical roll in regulating the voltage-dependent sodium currents in these cells (Westenbroek et al, 1989;Furuyama et al, 1993;Black et al, 1994;Whitaker et al, 2000;Novakovic et al, 2001). A positive shift in the voltage dependence of sodium channel inactivation should result in a larger population of sodium channels that are available to open at or near the resting membrane potential.…”

Section: Discussionmentioning

confidence: 99%

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Spampanato¹,

Kearney²,

Haan³

et al. 2004

J. Neurosci.

150

142

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A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFSϩ). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel ␣ subunit. The mutation decreased modulation of the ␣ subunit by ␤1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of ␤1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type ␣ subunit with the ␤1 or ␤3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for ␤ subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the ␣ and ␤1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

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Section: Discussionmentioning

confidence: 99%

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Spampanato¹,

Kearney²,

Haan³

et al. 2004

J. Neurosci.

150

142

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“…4 D-F and SI Appendix, Fig. S12) (37). A recent report by the Muotri laboratory provided a detailed analysis of neuronal maturation defects caused by MeCP2 mutations (20), noting the lower neurite aborization and electrophysiological defects in neurons differentiated from biallelic RTT-iPSCs.…”

Section: Retention and Reactivation Of Inactive X Chromosome In Rtt-imentioning

confidence: 99%

Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

Kim

Hysolli

Park

2011

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

197

183

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Rett syndrome (RTT) is one of the most prevalent female neurodevelopmental disorders that cause severe mental retardation. Mutations in methyl CpG binding protein 2 (MeCP2) are mainly responsible for RTT. Patients with classical RTT exhibit normal development until age 6-18 mo, at which point they become symptomatic and display loss of language and motor skills, purposeful hand movements, and normal head growth. Murine genetic models and postmortem human brains have been used to study the disease and enable the molecular dissection of RTT. In this work, we applied a recently developed reprogramming approach to generate a novel in vitro human RTT model. Induced pluripotent stem cells (iPSCs) were derived from RTT fibroblasts by overexpressing the reprogramming factors OCT4, SOX2, KLF4, and MYC. Intriguingly, whereas some iPSCs maintained X chromosome inactivation, in others the X chromosome was reactivated. Thus, iPSCs were isolated that retained a single active X chromosome expressing either mutant or WT MeCP2, as well as iPSCs with reactivated X chromosomes expressing both mutant and WT MeCP2. When these cells underwent neuronal differentiation, the mutant monoallelic or biallelelic RTT-iPSCs displayed a defect in neuronal maturation consistent with RTT phenotypes. Our in vitro model of RTT is an important tool allowing the further investigation of the pathophysiology of RTT and the development of the curative therapeutics.

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“…12 The sodium channel alpha subunit genes SCN1A, SCN2A and SCN3A are located at approximately 175 cM on chromosome 2, band 2q24. 15 These voltagegated sodium channels are expressed in neurons and glia throughout the central and peripheral nervous system 16,17 and have been highly conserved during invertebrate and vertebrate evolution. 18 Missense mutations in SCN1A and SCN2A have been identified in the inherited seizure disorder Generalized Epilepsy with Febrile Seizures Plus (GEFS+2, MIM 604236, 604233).…”

Section: Introductionmentioning

confidence: 99%

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

et al. 2003

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Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS þ . To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.

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Distribution of voltage-gated sodium channel ?-subunit and ?-subunit mRNAs in human hippocampal formation, cortex, and cerebellum

Cited by 125 publications

References 64 publications

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

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