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 language | English (US) |
|---|---|
| Pages (from-to) | 10022-10034 |
| Number of pages | 13 |
| Journal | Journal of Neuroscience |
| Volume | 24 |
| Issue number | 44 |
| DOIs | |
| State | Published - Nov 3 2004 |
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Keywords
- Channel
- Epilepsy
- Genetics
- Kinetic (kinetics)
- Mutant
- Sodium (Na)
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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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 journal › Article
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)
UR - http://www.scopus.com/inward/record.url?scp=20844446135&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20844446135&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2034-04.2004
DO - 10.1523/JNEUROSCI.2034-04.2004
M3 - Article
C2 - 15525788
AN - SCOPUS:20844446135
VL - 24
SP - 10022
EP - 10034
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 44
ER -