Characterization of aconitine-induced block of delayed rectifier K+ current in differentiated NG108-15 neuronal cells.

The effects of aconitine (ACO), a highly toxic alkaloid, on ion currents in differentiated NG108-15 neuronal cells were investigated in this study. ACO (0.3–30μM) suppressed the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC50 value of 3.1μM. The presence of ACO enhanced the rate and extent of IK(DR) inactivation, although it had no effect on the initial activation phase of IK(DR). It could shift the inactivation curve of IK(DR) to a hyperpolarized potential with no change in the slope factor. Cumulative inactivation for IK(DR) was also enhanced by ACO. Orphenadrine (30μM) or methyllycaconitine (30μM) slightly suppressed IK(DR) without modifying current decay. ACO (10μM) had an inhibitory effect on voltage-dependent Na+ current (INa). Under current-clamp recordings, ACO increased the firing and widening of action potentials in these cells. With the aid of the minimal binding scheme, the ACO actions on IK(DR) was quantitatively provided with a dissociation constant of 0.6μM. A modeled cell was designed to duplicate its inhibitory effect on spontaneous pacemaking. ACO also blocked IK(DR) in neuroblastoma SH-SY5Y cells. Taken together, the experimental data and simulations show that ACO can block delayed rectifier K+ channels of neurons in a concentration- and state-dependent manner. Changes in action potentials induced by ACO in neurons in vivo can be explained mainly by its blocking actions on IK(DR) and INa.