The beta-secretase BACE1 (Beta-site APP-Cleaving Enzyme 1) is notorious for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease (AD). Its activity represents therefore a major pharmacologic target in AD. However, a prerequisite for the safe administration of BACE1 inhibitors is a better understanding of the physiological functions of this secretase. Notably, the amyloid precursor protein (APP) is not the only substrate of BACE1. Among its newly identified substrates, beta-subunits of voltage-dependent ion channels are of particular importance, since their cleavage may have a direct impact on neuronal excitability. In fact, previous work from our and other laboratories has shown that BACE1-mediated cleavage of beta-2 and -4 subunits as well as non-proteolytic interactions with the alpha-subunit have considerable impact on Na channel expression, gating and overall neuronal excitability (reviewed in Huth & Alzheimer, Curr Alzheimer Res 2012). Here, we examined, whether BACE1 also exerts electrophysiologically relevant effects on KCNQ1 channels, which, in cardiac tissue, typically associate with the beta-subunit KCNE1 to generate the slow delayed rectifier K channel, I(Ks). Western blots showed that BACE1 protein is present in mouse heart tissue. Whole-cell recordings were performed in a heterologous expression system. Our main finding was that, apart from a rightward shift of the voltage-dependence of KCNQ1/E1 current activation, all other biophysical effects of BACE1 on channel kinetics and amplitude did not require proteolysis, since they were reproduced by a catalytically inactive BACE1 variant. Co-immunoprecipitation experiments strengthened the hypothesis that BACE1 might modulate KCNQ1 gating predominantly through a direct interaction with the alpha-subunit. When we used a cardiac action potential waveform as voltage command, co-expression of BACE1 enhanced KCNQ1/E1 currents during the plateau and falling phase, suggesting that BACE1 should have an impact on cardiac I(Ks). In conclusion, our study points to a novel and largely non-proteolytic function of BACE1 in cardiac electrophysiology.