The β1-subunit of Na(v)1.5 cardiac sodium channel is required for a dominant negative effect through α-α interaction. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue PLoS ONE Année : 2012

The β1-subunit of Na(v)1.5 cardiac sodium channel is required for a dominant negative effect through α-α interaction.

Résumé

Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Several mutations on the cardiac sodium channel Na(v)1.5 which are responsible for BrS lead to misfolded proteins that do not traffic properly to the plasma membrane. In order to mimic patient heterozygosity, a trafficking defective mutant, R1432G was co-expressed with Wild Type (WT) Na(v)1.5 channels in HEK293T cells. This mutant significantly decreased the membrane Na current density when it was co-transfected with the WT channel. This dominant negative effect did not result in altered biophysical properties of Na(v)1.5 channels. Luminometric experiments revealed that the expression of mutant proteins induced a significant reduction in membrane expression of WT channels. Interestingly, we have found that the auxiliary Na channel β(1)-subunit was essential for this dominant negative effect. Indeed, the absence of the β(1)-subunit prevented the decrease in WT sodium current density and surface proteins associated with the dominant negative effect. Co-immunoprecipitation experiments demonstrated a physical interaction between Na channel α-subunits. This interaction occurred only when the β(1)-subunit was present. Our findings reveal a new role for β(1)-subunits in cardiac voltage-gated sodium channels by promoting α-α subunit interaction which can lead to a dominant negative effect when one of the α-subunits shows a trafficking defective mutation.

Dates et versions

hal-00992871 , version 1 (19-05-2014)

Identifiants

Citer

Aurélie Mercier, Romain Clément, Thomas Harnois, Nicolas Bourmeyster, Jean-François Faivre, et al.. The β1-subunit of Na(v)1.5 cardiac sodium channel is required for a dominant negative effect through α-α interaction.. PLoS ONE, 2012, 7 (11), pp.e48690. ⟨10.1371/journal.pone.0048690⟩. ⟨hal-00992871⟩
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