TY - JOUR T1 - Inhibition of Astroglial Inwardly Rectifying Kir4.1 Channels by a Tricyclic Antidepressant, Nortriptyline JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 573 LP - 580 DO - 10.1124/jpet.106.112094 VL - 320 IS - 2 AU - Suwen Su AU - Yukihiro Ohno AU - Christoph Lossin AU - Hiroshi Hibino AU - Atsushi Inanobe AU - Yoshihisa Kurachi Y1 - 2007/02/01 UR - http://jpet.aspetjournals.org/content/320/2/573.abstract N2 - 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 μM) 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 (EK), 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 (Kd) of nortriptyline for Kir4.1 inhibition was 28.1 μMat EK. 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. The American Society for Pharmacology and Experimental Therapeutics ER -