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NEUROPHARMACOLOGY

Inhibition of Astroglial Inwardly Rectifying Kir4.1 Channels by a Tricyclic Antidepressant, Nortriptyline

Division of Cellular and Molecular Pharmacology, Department of Pharmacology, Graduate School of Medicine (S.S., Y.O., C.L., H.H., A.I., Y.K.) and the Center for Advanced Medical Engineering and Informatics (Y.K.), Osaka University, Osaka, Japan

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 (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 µMat 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.

Address correspondence to: Dr. Yoshihisa Kurachi, Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: ykurachi{at}pharma2.med.osaka-u.ac.jp

This article has been cited by other articles:

				K. Furutani, Y. Ohno, A. Inanobe, H. Hibino, and Y. Kurachi Mutational and In Silico Analyses for Antidepressant Block of Astroglial Inward-Rectifier Kir4.1 Channel Mol. Pharmacol., June 1, 2009; 75(6): 1287 - 1295. [Abstract] [Full Text] [PDF]