Imipramine inhibition of transient K+ current: an external open channel blocker preventing fast inactivation.
Rapidly inactivating K+ current (KA 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 KA channel blocker with a binding rate constant of 5.6 x 10(6) M-1 s-1 and an apparent dissociation constant of no more than 6 microM 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 KA current is not changed by imipramine. Moreover, the recovery of KA current after a step depolarization is accelerated in the presence of imipramine. These findings suggest insignificant binding of imipramine to the fast inactivated KA 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 KA channels during membrane depolarization.
Kuo
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CC
Department of Physiology, National Taiwan University College of Medicine, and Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan, Republic of China. cckuo@ha.mc.ntu.edu.tw
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000494:pharmacology; D001590:Benztropine / Q000494:pharmacology; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D004155:Diphenhydramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007099:Imipramine / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats
D000929:Antidepressive Agents, Tricyclic; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D001590:Benztropine; D004155:Diphenhydramine; D007099:Imipramine