Inhibition of a glial K channel by various tricyclic antidepressants

Abstract

Around 70% of brain tissue is composed of glial cell, which regulates the homeostasis of various neurotransmitters, ions and water in the brain. However, little studies have been performed on the effects of CNS-acting drugs on glial function. We have examined the effect of various tricyclic antidepressant agents: amitriptyline, imipramine, nortriptyline, and desipramine, on a K⁺channel responsible for the glial K⁺-buffering action. The glial K⁺ -buffering channels are composed either of homomeric assembly of Kir4.1 or of heteromeric assembly of Kir4.1 and Kir5.1. In this study, Kir4.1 homomeric channels were exogeneously expressed in tsA201 cells and whole-cell currents were recorded using a patch-clamp technique. Application of each of the various tricyclic antidepressants immediately and reversibly caused a reduction of inward and outward currents through this channel. The inhibition was stronger as the membrane was more depolarized. Development of the current blockage was well fitted with a single exponential function. These results indicate that the block of Kir4.1 channels by these antidepressants was clearly in a voltage- and time-dependent fashion. Thus, various tricyclic antidepressants may act as inhibitors at the glial Kir4.1 channels. We conclude that the inhibition of the glial Kir4.1 channels by these drugs underlies the therapeutic effects and some of the side effects, particularly seizures in overdose. [J Physiol Sci. 2006;56 Suppl:S113]