Mutations in cardiac Na
+
channel Na
v
1.5 cause cardiac arrhythmias and sudden death. The cardiac Na
+
channel functions as a protein complex, however, its complete components remain to be fully elucidated. A yeast two-hybrid screen identified a new candidate Na
v
1.5-interacting protein, αB-crystallin. GST-pull-down, co-immunoprecipitation and immunostaining analyses validated the interaction between Na
v
1.5 and αB-crystallin. Overexpression of αB-crystallin significantly increased peak sodium current (
I
Na
) density, and the underlying molecular mechanism is the increased cell surface expression level of Na
v
1.5 via reduced internalization of cell surface Na
v
1.5 and ubiquitination of Na
v
1.5. Knockout of αB-crystallin expression significantly decreased the cell-surface expression level of Na
v
1.5. αB-crystallin interacted with Nedd4-2, however, a catalytically inactive Nedd4-2-C801S mutant reduced the interaction between αB-crystallin and Nedd4-2 and also blocked the increase of peak I
Na
density by αB-crystallin. Na
v
1.5 mutation V1980A at the interaction site for Nedd4-2 eliminated the effect of αB-crystallin on reduction of Na
v
1.5 ubiquitination and increases of
I
Na
density. The data suggest that the interactions between αB-crystallin and functionally active Nedd4-2 and between αB-crystallin and Na
v
1.5 are critical to increased
I
Na
density by αB-crystallin. Multiple mutations in αB-crystallin have been associated with human diseases. Two mutations, R109H and R151X, eliminated the effect of αB-crystallin on
I
Na
.
This study identifies αB-crystallin as a new binding partner for Na
v
1.5. αB-crystallin interacts with Na
v
1.5 and increases
I
Na
by modulating the expression level and internalization of cell surface Na
v
1.5 and ubiquitination of Na
v
1.5, which requires the protein-protein interactions between αB-crystallin and Na
v
1.5 and between αB-crystallin and functionally active Nedd4-2.
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