Open channel block of Kv1.4 potassium channels by aripiprazole

Aripiprazole is a quinolinone derivative approved as an atypical antipsychotic drug for the treatment of schizophrenia and bipolar disorder. It acts as with partial agonist activities at the dopamine D2 receptors. Although it is known to be relatively safe for patients with cardiac ailments, less is...

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Published inThe Korean journal of physiology & pharmacology Vol. 24; no. 6; pp. 545 - 553
Main Authors Park, Jeaneun, Cho, Kwang-Hyun, Lee, Hong Joon, Choi, Jin-Sung, Rhie, Duck-Joo
Format Journal Article
LanguageKorean
Published 대한생리학회-대한약리학회 30.11.2020
The Korean Journal of Physiology & Pharmacology Editorial Office
Subjects
Open channel block
Atypical antipsychotics
Kv1.4 channel
Inactivation kinetics
Use dependent
4 channel
Kv1
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Summary:Aripiprazole is a quinolinone derivative approved as an atypical antipsychotic drug for the treatment of schizophrenia and bipolar disorder. It acts as with partial agonist activities at the dopamine D2 receptors. Although it is known to be relatively safe for patients with cardiac ailments, less is known about the effect of aripiprazole on voltage-gated ion channels such as transient A-type K+ channels, which are important for the repolarization of cardiac and neuronal action potentials. Here, we investigated the effects of aripiprazole on Kv1.4 currents expressed in HEK293 cells using a whole-cell patch-clamp technique. Aripiprazole blocked Kv1.4 channels in a concentration-dependent manner with an IC50 value of 4.4 μM and a Hill coefficient of 2.5. Aripiprazole also accelerated the activation (time-to-peak) and inactivation kinetics. Aripiprazole induced a voltage-dependent (δ = 0.17) inhibition, which was use-dependent with successive pulses on Kv1.4 currents without altering the time course of recovery from inactivation. Dehydroaripiprazole, an active metabolite of aripiprazole, inhibited Kv1.4 with an IC50 value of 6.3 μM (p < 0.05 compared with aripiprazole) with a Hill coefficient of 2.0. Furthermore, aripiprazole inhibited Kv4.3 currents to a similar extent in a concentration-dependent manner with an IC50 value of 4.9 μM and a Hill coefficient of 2.3. Thus, our results indicate that aripiprazole blocked Kv1.4 by preferentially binding to the open state of the channels.
Bibliography:KISTI1.1003/JNL.JAKO202030161655743
ISSN:1226-4512
2093-3827