Abstract
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.
Footnotes
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This work was partly supported by the Leading Project for Biosimulation “Development of Models for Disease and Drug Action” (to Y.K.) and by a Grant-in-Aid for Scientific Research on Priority Areas 17081012 (to H.H.) from the Ministry of Education, Science, Sports and Culture of Japan.
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S.S. and Y.O. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112094.
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ABBREVIATIONS: Kir, inward rectifying K+; TCA, tricyclic antidepressant; GFP, green fluorescent protein.
- Received August 7, 2006.
- Accepted October 26, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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