Mutation E87Q of the ß1-subunit impairs the maturation of the cardiac voltage-dependent sodium channel.

Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These membrane integral proteins are composed by a pore-forming α-subunit, and one or more auxiliary ß subunits. Mutation E87Q of the ß1 subunit is correlated with Brugada syndrome, a genetic disease characterised by ventricular fibrillation, right precordial ST segment elevation on ECG and sudden cardiac death. Heterologous expression of E87Q-ß1 subunit in CHO cells determines a reduced sodium channel functional expression. The effect the E87Q mutation of the ß1 subunit on sodium currents and α protein expression is correlated with a reduced availability of the mature form of the α subunit in the plasma membrane. This finding offers a new target for the treatment of the Brugada syndrome, based on protein maturation management. This work highlights the role played by the ß1 subunit in the maturation and expression of the entire sodium channel complex and underlines how the defective interaction between the sodium channel constituents could lead to a disabling pathological condition.