Biophysical Investigation of Sodium Channel Interaction with β-Subunit Variants Associated with Arrhythmias

Voltage-gated sodium (Na) channels help regulate electrical activity of the plasma membrane. Mutations in associated subunits can result in pathological outcomes. Here we examined the interaction of Na channels with cardiac arrhythmia-linked mutations in and , two genes that encode auxiliary β-subunits. To investigate changes in and function, we combined three-dimensional X-ray crystallography with electrophysiological measurements on Na1.5, the dominant subtype in the heart. alters channel activity, whereas does not have an apparent effect. Structurally, the perturbation alters hydrophobic packing of the subunit with major structural changes and causes a thermal destabilization of the folding. In contrast, leads to structural changes but overall protein stability is unaffected. data suggest a functionally important region in the interaction between Na1.5 and β4 that, when disrupted, could lead to channel dysfunction. A lack of apparent functional effects of on Na1.5 suggests an alternative working mechanism, possibly through other Na channel subtypes present in heart tissue. Indeed, mapping the structural variations of onto neuronal Na channel structures suggests altered interaction patterns.