Voltage-dependent sodium channel complexes consist of a pore-forming and voltage-sensing a-subunit and one or two b-subunits. The latter are type I transmembrane proteins with a broad spectrum of functions in channel expression and surface targeting, in channel electrophysiology and, notably, in cell-adhesion of excitable and non-excitable cells. Like the amyloid-precursor protein (APP), b-subunits are substrates for sequential cleavage either by a- and g-secretase, or by b- and g-secretase. The talk will focus on the processing of b-subunits by the amyloidogenic b-secretase, BACE1, which is up-regulated in Alzheimer's disease and is considered a highly promising pharmacologic target. Based on data from BACE1-deficient or over-expressing mice and from heterologous expression systems, the talk will summarize our growing understanding of how BACE1-mediated cleavage of b-subunits interferes with their multiple roles in the modulation of fast, persistent and resurgent Na⁺ currents.