Abstract
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 β subunits. Mutation E87Q of the β1 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-β1 subunit in CHO cells determines a reduced sodium channel functional expression. The effect the E87Q mutation of the β1 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 β1 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.
Highlights
Voltage gated sodium channels (NaChs) open and close on a millisecond time scale in response to changes in cell membrane potential
Co-expression of Nav1.5 and WT-β1 (Fig. 1B and D) significantly increased sodium current over Nav1.5 alone, while currents recorded with Nav1.5 co-expressed with E87Q-β1 (Fig. 1C and D) were not different from Nav1.5 alone
Our results confirm that mutation E87Q abolishes the increment of functional expression of NaCh currents induced by the expression of the WT-β1subunit, as well as the shift of the activation curve, as previously reported[29]
Summary
Voltage gated sodium channels (NaChs) open and close on a millisecond time scale in response to changes in cell membrane potential. Nine different voltage-gated α subunits designated Nav1.1–Nav1.9, and a related, non-voltage-gated atypical isoform named Navx, have been found in mammals, each encoded by a different gene[19]. These genes produce polypeptides with a high degree of sequence identity, but a distinctive tissue specificity expression for a review see ref. We pointed out that the effect of the E87Q mutation of the β1 subunit on sodium current and Nav1.5 protein expression is correlated with a reduction of mature Nav1.5 α subunit availability in the cell membrane This finding offers a new target for the treatment of the Brugada syndrome, based on a protein maturation management
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