A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction

J. Spampanato, J. A. Kearney, G. De Haan, D. P. McEwen, A. Escayg, I. Aradi, B. T. MacDonald, S. I. Levin, I. Soltesz, P. Benna, E. Montalenti, L. L. Isom, A. L. Goldin, M. H. Meisler*

*Corresponding author for this work

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionary conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resultingin a 10 mV difference between the wild-type and mutant channels in the presence of β1. 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 α subunit with the β1 or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

Original languageEnglish (US)
Pages (from-to)10022-10034
Number of pages13
JournalJournal of Neuroscience
Volume24
Issue number44
DOIs
StatePublished - Nov 3 2004

Fingerprint

Sodium Channels
Epilepsy
Mutation
Action Potentials
Seizures
Architectural Accessibility
Aspartic Acid
Cell Communication
Oocytes
Yeasts
Neurons
Peptides
Injections

Keywords

  • Channel
  • Epilepsy
  • Genetics
  • Kinetic (kinetics)
  • Mutant
  • Sodium (Na)

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Spampanato, J. ; Kearney, J. A. ; De Haan, G. ; McEwen, D. P. ; Escayg, A. ; Aradi, I. ; MacDonald, B. T. ; Levin, S. I. ; Soltesz, I. ; Benna, P. ; Montalenti, E. ; Isom, L. L. ; Goldin, A. L. ; Meisler, M. H. / A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 44. pp. 10022-10034.
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abstract = "A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionary conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resultingin a 10 mV difference between the wild-type and mutant channels in the presence of β1. 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 α subunit with the β1 or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.",
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author = "J. Spampanato and Kearney, {J. A.} and {De Haan}, G. and McEwen, {D. P.} and A. Escayg and I. Aradi and MacDonald, {B. T.} and Levin, {S. I.} and I. Soltesz and P. Benna and E. Montalenti and Isom, {L. L.} and Goldin, {A. L.} and Meisler, {M. H.}",
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Spampanato, J, Kearney, JA, De Haan, G, McEwen, DP, Escayg, A, Aradi, I, MacDonald, BT, Levin, SI, Soltesz, I, Benna, P, Montalenti, E, Isom, LL, Goldin, AL & Meisler, MH 2004, 'A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction', Journal of Neuroscience, vol. 24, no. 44, pp. 10022-10034. https://doi.org/10.1523/JNEUROSCI.2034-04.2004

A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction. / Spampanato, J.; Kearney, J. A.; De Haan, G.; McEwen, D. P.; Escayg, A.; Aradi, I.; MacDonald, B. T.; Levin, S. I.; Soltesz, I.; Benna, P.; Montalenti, E.; Isom, L. L.; Goldin, A. L.; Meisler, M. H.

In: Journal of Neuroscience, Vol. 24, No. 44, 03.11.2004, p. 10022-10034.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for β subunit interaction

AU - Spampanato, J.

AU - Kearney, J. A.

AU - De Haan, G.

AU - McEwen, D. P.

AU - Escayg, A.

AU - Aradi, I.

AU - MacDonald, B. T.

AU - Levin, S. I.

AU - Soltesz, I.

AU - Benna, P.

AU - Montalenti, E.

AU - Isom, L. L.

AU - Goldin, A. L.

AU - Meisler, M. H.

PY - 2004/11/3

Y1 - 2004/11/3

N2 - A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionary conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resultingin a 10 mV difference between the wild-type and mutant channels in the presence of β1. 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 α subunit with the β1 or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

AB - A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFS+). The mutation, D1866Y, alters an evolutionary conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel α subunit. The mutation decreased modulation of the α subunit by β1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resultingin a 10 mV difference between the wild-type and mutant channels in the presence of β1. 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 α subunit with the β1 or β3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for β subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the α and β1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

KW - Channel

KW - Epilepsy

KW - Genetics

KW - Kinetic (kinetics)

KW - Mutant

KW - Sodium (Na)

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