Imipramine Inhibition of Transient K + Current: An External Open Channel Blocker Preventing Fast Inactivation

Abstract

Rapidly inactivating K + current (K A current) is recorded from rat hippocampal neurons by whole-cell patch-clamp technique and suitable voltage protocols. It is found that imipramine, a commonly prescribed tricyclic antidepressant, is an open K A channel blocker with a binding rate constant of 5.6 × 10 6 M −1 s −1 and an apparent dissociation constant of no more than 6 μM if applied extracellularly in pH 7.4. The inhibitory effect is more pronounced in more alkaline extracellular solution, suggesting that the neutral form of imipramine is much more active than the charged form. In contrast, intracellular imipramine shows no inhibitory effect. Furthermore, the inhibitory effect of imipramine is antagonized by external but not internal K +. These findings suggest an imipramine binding site located close to the external pore mouth. It is also found that the inactivation curve of K A current is not changed by imipramine. Moreover, the recovery of K A current after a step depolarization is accelerated in the presence of imipramine. These findings suggest insignificant binding of imipramine to the fast inactivated K A channel. The selective binding of imipramine to only the activated but not the deactivated or inactivated states seems to suggest continual gating conformational changes in the external pore mouth of these neuronal K A channels during membrane depolarization.