Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels

Spampanato, Jay; Escayg, Andrew; Meisler, Miriam H.; Goldin, Alan L.

doi:10.1016/s0306-4522(02)00698-x

Cited by 93 publications

(76 citation statements)

References 42 publications

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“…Such a shift in steady-state activation and inactivation curves would lead to depolarization of the window current, defined as the voltage range at which a small percentage of channels are persistently active. Previous reports suggest that point mutations of two Na v isoforms that cause similar shifts in window current voltage range may be responsible for such maladies as epilepsy and LQTS (25,26). Such changes in window current will cause a shift in the voltages at which a persistent Na ϩ current exists relative to the threshold and resting membrane potentials, and this could increase susceptibility to altered excitability.…”

Section: Discussionmentioning

confidence: 99%

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Montpetit

Stocker

Schwetz

et al. 2009

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

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Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2 (؊/؊) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na ؉ channels were altered consistently in ST8sia2 (؊/؊) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation. action potentials ͉ cardiomyocyte ͉ glycomics ͉ ion channels ͉ sialic acids

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Section: Discussionmentioning

confidence: 99%

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Montpetit

Stocker

Schwetz

et al. 2009

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

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“…To determine the effects of the D1866Y mutation on the functional properties of the sodium channel, the mutation was introduced into the previously described orthologous full-length rat Na v 1.1 cDNA clone (Smith and Goldin, 1998;Spampanato et al, 2003). The biophysical properties of the mutant channels were characterized using the Xenopus oocyte expression system, for the following reasons.…”

Section: The D1866y Mutation Does Not Alter the Voltage Dependence Ofmentioning

confidence: 99%

“…Second, the ␤1 subunit has a clear and easily quantifiable effect on the properties of ␣ subunit sodium channels in oocytes, so that we could reliably determine whether the ␣ subunit mutation altered modulation by ␤1. Third, the data could be directly compared with our previous results for three other GEFSϩ mutations with respect to both the effects on sodium channel properties and the predicted effects on neuronal firing using a computational model (Spampanato et al, 2001(Spampanato et al, , 2003(Spampanato et al, , 2004. It is important to note that although the oocyte expression system provides a powerful means to determine biophysical differences between mutant and wild-type channels, there have been functional differences as well as similarities between observations in oocytes and in mammalian-transfected cells for some mutants (Spampanato et al, 2001(Spampanato et al, , 2003Lossin et al, 2002).…”

Section: The D1866y Mutation Does Not Alter the Voltage Dependence Ofmentioning

confidence: 99%

“…GenBank accession numbers are from Escayg et al (2001). Because shifts in the voltage dependence of activation are a common diseasecausing mechanism underlying known sodium channelopathies (Cummins et al, 1993;Mitrovic et al, 1995;Green et al, 1998;Rook et al, 1999;Smith and Goldin, 1999), including three mutations associated with GEFSϩ (Lossin et al, 2003;Spampanato et al, 2003), we first characterized the voltage dependence of channel activation. Peak current amplitudes were recorded as described in Materials and Methods and fit with a two-state Boltzmann equation (Fig.…”

Section: The D1866y Mutation Does Not Alter the Voltage Dependence Ofmentioning

confidence: 99%

“…Most of these are located within or adjacent to transmembrane segments or in the pore region of the channel. The biophysical characteristics of eight mutations have been examined, revealing an array of phenotypic variations in channel function (Spampanato et al, 2001(Spampanato et al, , 2003Lossin et al, 2002Lossin et al, , 2003Cossette et al, 2003). Functional characterization of additional disease alleles of SCN1A can further our understanding of the structure-function relationships of the channel protein.…”

Section: Introductionmentioning

confidence: 99%

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

Spampanato¹,

Kearney²,

Haan³

et al. 2004

J. Neurosci.

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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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Molecular Basis of Inherited Epilepsy

George

2004

Arch Neurol

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pilepsy is a common, paroxysmal, and heterogeneous neurological disorder. Many factors, including complex genetic influences, contribute to the pathogenesis of epilepsy. However, several epilepsy syndromes are caused by mutations in single genes (Table ). Most epilepsy-associated genes that have been identified within the past 5 years encode ion channels. This review illustrates the progress in defining the molecular basis of inherited epilepsies and highlights conditions caused by dysfunctional ion channels.

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Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels

Cited by 93 publications

References 42 publications

Regulated and aberrant glycosylation modulate cardiac electrical signaling

Regulated and aberrant glycosylation modulate cardiac electrical signaling

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

Molecular Basis of Inherited Epilepsy

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