Inhibition by bis(7)-tacrine of native delayed rectifier and KV1.2 encoded potassium channels

Bis(7)-tacrine [bis(7)-tetrahydroaminacrine] acts as an AChE inhibitor and also exerts modulatory effects on many ligand-gated ion channels and voltage-gated Ca2+ and K+ channels. It has been reported previously that tacrine and some other AChE inhibitors suppressed IK(A) in central and peripheral neurons. The present study aimed to explore whether bis(7)-tacrine could modulate the function of native delayed rectifier potassium channels in DRG neurons and KV1.2 encoded potassium channels expressed in oocytes. We found that both delayed rectifier potassium currents (IK(DR)) in rat DRG neurons and the currents recorded from oocytes expressing KV1.2 (IK(KV1.2)IK(KV1.2)) were suppressed by bis(7)-tacrine, the potency of which was two orders greater than that of tacrine. The IC50 values for bis(7)-tacrine and tacrine inhibition of IK(KD) in DRG neurons were 0.72 ± 0.05 and 58.3 ± 3.7 μM, respectively; while the two agents inhibited IK(KV1.2)IK(KV1.2) in oocytes with an IC50 of 0.24 ± 0.06 and 102.1 ± 21.5 μM, respectively. The possible mechanism for bis(7)-tacrine inhibition of IK(A) and IK(KV1.2)IK(KV1.2) was identified as the suppression of their activation, inactivation.