2-Aminoethoxydiphenyl borate (2-APB), a boron-containing compound, is a multitarget compound with potential as a drug precursor and exerts various effects in systems of the human body. Ion channels are among the reported targets of 2-APB. The effects of 2-APB on voltage-gated potassium channels (KV) have been reported, but the types of KV channels that 2-APB inhibits and the inhibitory mechanism remain unknown. In this paper, we discovered that 2-APB acted as an inhibitor of three representative human KV1 channels. 2-APB significantly blocked A-type Kv channel KV1.4 in a concentration-dependent manner, with an IC50 of 67.3 μM, while it inhibited the delayed outward rectifier channels KV1.2 and KV1.3, with IC50s of 310.4 μM and 454.9 μM, respectively. Further studies on KV1.4 showed that V549, T551, A553, and L554 at the cavity region and N-terminal played significant roles in 2-APB's effects on the KV1.4 channel. The results also indicated the importance of fast inactivation gating in determining the different effects of 2-APB on three channels. Interestingly, a current facilitation phenomenon by a short prepulse after 2-APB application was discovered for the first time. The docked modeling revealed that 2-APB could form hydrogen bonds with different sites in the cavity region of three channels, and the inhibition constants showed a similar trend to the experimental results. These findings revealed new molecular targets of 2-APB and demonstrated that 2-APB's effects on KV1 channels might be part of the reason for the diverse bioactivities of 2-APB in the human body and in animal models of human disease.
Keywords: 2-APB; KV1.2; KV1.3; KV1.4; potassium channel.