Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/44329
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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
Rights: Copyright © 2007 IBRO Published by Elsevier Ltd.
RMID: 0020072309
DOI: 10.1016/j.neuroscience.2007.05.038
Appears in Collections:Molecular and Biomedical Science publications

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