Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/44329
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: eneralized epilepsy with febrile seizures plus-associated sodium channel β1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function
Other Titles: Generalized epilepsy with febrile seizures plus-associated sodium channel beta1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function
Author: Xu, R.
Thomas, E.
Gazina, E.
Richards, K.
Quick, M.
Wallace, R.
Harkin, L.
Heron, S.
Berkovic, S.
Scheffer, I.
Mulley, J.
Petrou, S.
Citation: Neuroscience, 2007; 148(1):164-174
Publisher: Pergamon-Elsevier Science Ltd
Issue Date: 2007
ISSN: 0306-4522
1873-7544
Statement of
Responsibility: 
R. Xu, E.A. Thomas, E.V. Gazina, K.L. Richards, M. Quick, R.H. Wallace, L.A. Harkin, S.E. Heron, S.F. Berkovic, I.E. Scheffer, J.C. Mulley, S. Petrou
Abstract: Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in individuals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch clamp studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis.
Keywords: Brain
Synapses
Cell Line
Humans
Epilepsy, Generalized
Seizures, Febrile
Genetic Predisposition to Disease
Sodium Channels
Nerve Tissue Proteins
Protein Subunits
Patch-Clamp Techniques
Transfection
Ion Channel Gating
Synaptic Transmission
Brain Chemistry
Membrane Potentials
Action Potentials
Mutation
NAV1.1 Voltage-Gated Sodium Channel
Voltage-Gated Sodium Channel beta-1 Subunit
Rights: Copyright © 2007 IBRO Published by Elsevier Ltd.
DOI: 10.1016/j.neuroscience.2007.05.038
Published version: http://dx.doi.org/10.1016/j.neuroscience.2007.05.038
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.