Reversible Block of BK Channels by Piperine

Abstract

Increasing evidence shows antitumor efficacy of potassium channel blockers, with potential relevance in anticancer therapeutics (1). Altered expression of BK channels has been reported in different tumor types resulting in sustained proliferation and migration of cancer cells (2). Piperine, a primary pungent alkaloid found in black pepper has been proposed as a cancer chemopreventive agent which works by interrupting cancer development pathways (3). Here, we characterized the effects of piperine on BKα channels in the absence and presence of regulatory subunits using patch-clamp electrophysiology in heterologous expression systems. We observed a clear antagonist activity of piperine on pore-forming BKα channels with an IC50 of 5 ± 1 μM. This inhibition exhibited a rapid onset (τ = 2.2 ± 0.3 s) and was completely reversible after a slow recovery (τ = 21 ± 2 s). The IC50 values did not change significantly over a range of voltages, suggesting that piperine does not function as an open-channel blocker. Moreover, elevating the internal calcium significantly diminished the block of BKα channels by piperine. The blocking action of piperine persisted in BK-G311S mutant channels, suggesting that its site of action is different from that of fungal alkaloids (e.g. paxilline, penitrem A). Intriguingly, the efficacy of the piperine inhibition persisted in BK channels containing BKβ subunits and was significantly attenuated in the presence of BKγ subunits. In summary, our data suggest that piperine is a novel blocker of BK channels exerting differential effects that depend on the accessory subunits. Evaluation of the anti-proliferative activity of piperine in various cancer cell lines, that might be mediated via blockade of BK channels, is currently underway. 1. Huang and Jan. JCB 2014, 206:151. 2. Oeggerli et al. Plos One 2012, 7:e41664. 3. Rather and Bhagat. Front Cell Dev Biol 2018, 6:10.