Inhibitory Effects of 2-Aminoethoxydiphenyl Borate (2-APB) on Three KV1 Channel Currents

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 (K-V) have been reported, but the types of K-V 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 K(V)1 channels. 2-APB significantly blocked A-type Kv channel K(V)1.4 in a concentration-dependent manner, with an IC50 of 67.3 mu M, while it inhibited the delayed outward rectifier channels K(V)1.2 and K(V)1.3, with IC(50)s of 310.4 mu M and 454.9 mu M, respectively. Further studies on K(V)1.4 showed that V549, T551, A553, and L554 at the cavity region and N-terminal played significant roles in 2-APB's effects on the K(V)1.4 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 K(V)1 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.

Automated summary

2-Aminoethoxydiphenyl borate (2-APB), a multitarget compound, acts as an inhibitor of three human K(V)1 channels. The effects of 2-APB on K(V)1.4 channel depend on specific amino acids in the cavity region and N-terminal. This study reveals new molecular targets and provides insights into the diverse bioactivities of 2-APB.