Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline

The inwardly rectifying K+ ( Kir) channel Kir4.1 is responsible for astroglial K+ buffering. We examined the effects of nortriptyline, a tricyclic antidepressant ( TCA), on Kir4.1 channel currents heterologously expressed in HEK293T cells, using a whole-cell patch-clamp technique. Nortriptyline ( 3 - 300 mu M) reversibly inhibited Kir4.1 currents in a concentration- dependent manner, whereas it marginally affected neuronal Kir2.1 currents. The inhibition of Kir4.1 channels by nortriptyline depended on the voltage difference from the K+ equilibrium potential ( E K), with greater potency at more positive potentials. Blocking kinetics of the drug could be described by first-order kinetics, where dissociation of the drug slowed down and association accelerated as the membrane was depolarized. The dissociation constant ( K-d) of nortriptyline for Kir4.1 inhibition was 28.1 mu M at E-K. Other TCAs, such as amitriptyline, desipramine, and imipramine, also inhibited Kir4.1 currents in a similar voltage-dependent fashion. This study shows for the first time that nortriptyline and related TCAs cause a concentration-, voltage-, and time-dependent inhibition of astroglial K+- buffering Kir4.1 channels, which might be involved in therapeutic and/or adverse actions of the drugs.