Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation.

Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Research Abstract Details 

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Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Abstract Text:

Kristopher M Kahlig,Sunita N Misra,Alfred L George,

Mutations in SCN1A (encoding the neuronal voltage-gated sodium channel alpha1 subunit, Na(V)1.1, or SCN1A) are associated with genetic epilepsy syndromes including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy. Here, we present the formulation and use of a computational model for SCN1A to elucidate molecular mechanisms underlying the increased persistent sodium current exhibited by the GEFS+ mutant R1648H. Our model accurately reproduces all experimentally measured SCN1A whole-cell biophysical properties including biphasic whole-cell current decay, channel activation, and entry into and recovery from fast and slow inactivation. The model predicts that SCN1A open-state inactivation results from a two-step process that can be conceptualized as initial gate closure, followed by recruitment of a mechanism ("latch") to stabilize the inactivated state. Selective impairment of the second latching step results in an increase in whole-cell persistent current similar to that observed for the GEFS+ mutant R1648H. These results provide a deeper level of understanding of mutant SCN1A dysfunction in an inherited epilepsy syndrome, which will enable more precise computational studies of abnormal neuronal activity in epilepsy and may help guide new targeted therapeutic strategies.

Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Publishing Authors By Initials

KM Kahlig,SN Misra,AL George,

For similar genetic processes: gene expression regulation: up-regulation research abstracts see: genetic processes: gene expression regulation: up-regulation research

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Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of neuroscience : the official journal

VOLUME: 26

Page Numbers: 10958-66

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 25

MONTH: Oct

YEAR: 2006

Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Information

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LANGUAGE: eng

NlmUniqueID: 8102140

Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: genetics

Chemical & Substance for Abstract: Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation. Information

Substance Name: sodium channel, voltage-gated, type I, a

Registry Number: 0

Grant and Affiliation Information for Impaired inactivation gate stabilization predicts increased persistent current for an epilepsy-associated SCN1A mutation.

AFFILIATION: Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.

Country: United States

AGENCY: United States NIMH

GRANT: T32-MH065215

ACRONYM: MH

MEDLINETA: J Neurosci

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