Blockade of Kv1.5 by paroxetine, an antidepressant drug

• 영문명: Blockade of Kv1.5 by paroxetine, an antidepressant drug
• 발행기관: 대한생리학회-대한약리학회
• 저자명: Hyang Mi Lee Sang June Hahn Bok Hee Choi
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제20권 제1호, 75~82쪽, 전체 8쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2016.01.01

영문 초록

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported to have an effect on several ion channels including human ether-a-go-gorelated 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 µM 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 d of 0.32. The binding (k₊₁) and unbinding (k_–1) rate constants for paroxetine-induced block of Kv1.5 were 4.9 µM^–1s^–1 and 16.1 s^–1, respectively. The theoretical K_D value derived by k_–1/k₊₁ yielded 3.3 µM. 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.

키워드

Kv1.5 Open channel block Paroxetine Selective serotonin reuptake inhibitor Shaker-type K⁺ channel