Blockade of Kv1.5 by paroxetine, an antidepressant drug.
10.4196/kjpp.2016.20.1.75
- Author:
Hyang Mi LEE
1
;
Sang June HAHN
;
Bok Hee CHOI
Author Information
1. Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54097, Korea. bhchoi@jbnu.ac.kr
- Publication Type:Original Article
- Keywords:
Kv1.5;
Open channel block;
Paroxetine;
Selective serotonin reuptake inhibitor;
Shaker-type K+ channel
- MeSH:
Animals;
Clone Cells;
Cricetinae;
Cricetulus;
Female;
Humans;
Inhibitory Concentration 50;
Ion Channels;
Kinetics;
Neurons;
Ovary;
Paroxetine*;
Patch-Clamp Techniques;
Rats;
Serotonin;
Tail
- From:The Korean Journal of Physiology and Pharmacology
2016;20(1):75-82
- CountryRepublic of Korea
- Language:English
-
Abstract:
Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported to have an effect on several ion channels including human ether-a-go-go-related gene in a SSRI-independent manner. These results suggest that paroxetine may cause side effects on cardiac system. In this study, we investigated the effect of paroxetine on Kv1.5, which is one of cardiac ion channels. The action of paroxetine on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Paroxetine reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an IC50 value and a Hill coefficient of 4.11 microM and 0.98, respectively. Paroxetine accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to 0 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance delta of 0.32. The binding (k(+1)) and unbinding (k(-1)) rate constants for paroxetine-induced block of Kv1.5 were 4.9 microM(-1)s(-1) and 16.1 s-1, respectively. The theoretical K(D) value derived by k(-1)/k(+1) yielded 3.3 microM. Paroxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of paroxetine, were superimposed. Inhibition of Kv1.5 by paroxetine was use-dependent. The present results suggest that paroxetine acts on Kv1.5 currents as an open-channel blocker.
