The contribution of secretase cleavage to voltage-gated Na+ channel β1-subunit function in breast cancer cells

Voltage-gated Na+ channels (VGSCs) are complexes consisting of Na+-conducting α-subunits and auxiliary β-subunits (β1-β4, encoded by SCN1B - SCN4B). Na+ influx depolarises excitable tissue and VGSC mutations are common in epilepsy and arrhythmia. VGSCs are aberrantly expressed in cancer. β1 is upregulated in invasive breast cancer and enhances metastasis in vivo. The mechanism underlying β1-induced metastatic cell behaviour is not clear, highlighting the need for better understanding. β-subunits modulate α-subunits and induce cell adhesion. Sequential cleavage of β1 by α-/β-secretase and γ-secretase releases an intracellular domain. The impact of secretase cleavage on β1 function is unknown. The hypothesis of this study was that secretase cleavage regulates β1 subcellular localisation and function, i.e. α-subunit modulation and cell adhesion, in breast cancer cells. Methods used included various types of microscopy and patch clamp electrophysiology. In summary, this study provided further mechanistic insight into the function of β1 in breast cancer cells and the possible contribution of secretase cleavage-mediated regulation.