We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.

Background and purpose: Two-pore-domain potassium (K 2P ) channels mediate potassium background (or 'leak') currents, controlling excitability by stabilizing membrane potential below firing threshold and expediting repolarization. Inhibition of K 2P currents permits membrane potential depolarization and excitation. As expected for key regulators of excitability, leak channels are under tight control from a plethora of stimuli. Recently, signalling via protein tyrosine kinases (TKs) has been implicated in ion channel modulation. The objective of this study was to investigate TK regulation of K 2P channels. Experimental approach: The two-electrode voltage clamp technique was used to record K 2P currents in Xenopus oocytes. In addition, K 2P channels were studied in Chinese hamster ovary (CHO) cells using the whole-cell patch clamp technique. Key results: Here, we report inhibition of human K 2P 3.1 (TASK-1) currents by the TK antagonist, genistein, in Xenopus oocytes (IC 50 ¼ 10.7 mM) and in CHO cells (IC 50 ¼ 12.3 mM). The underlying molecular mechanism was studied in detail. hK 2P 3.1 was not affected by genistin, an inactive analogue of genistein. Perorthovanadate, an inhibitor of tyrosine phosphatase activity, reduced the inhibitory effect of genistein. Current reduction was voltage independent and did not require channel protonation at position H98 or phosphorylation at the single TK phosphorylation site, Y323. Among functional hK 2P family members, genistein also reduced K 2P 6.1 (TWIK-2), K 2P 9.1 (TASK-3) and K 2P 13.1 (THIK-1) currents, respectively. Conclusions and implications: Modulation of K 2P channels by the TK inhibitor, genistein, represents a novel molecular mechanism to alter background K þ currents.