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.

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.

Here, we report inhibition of human K_2P3.1 (TASK‐1) currents by the TK antagonist, genistein, in Xenopus oocytes (IC₅₀=10.7 μM) and in CHO cells (IC₅₀=12.3 μM). The underlying molecular mechanism was studied in detail. hK_2P3.1 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_2P6.1 (TWIK‐2), K_2P9.1 (TASK‐3) and K_2P13.1 (THIK‐1) currents, respectively.

Modulation of K_2P channels by the TK inhibitor, genistein, represents a novel molecular mechanism to alter background K⁺ currents.

British Journal of Pharmacology (2008) 154, 1680–1690; doi:10.1038/bjp.2008.213; published online 2 June 2008