Blocking effect of fluoxetine on hERG potassium channel activity and inhibition by phorbol-12-myristate-13-acetate
10.3867/j.issn.1000-3002.2014.06.005
- VernacularTitle:氟西汀对hERG钾通道的阻断作用及佛波酯的抑制作用
- Author:
Xijie WANG
;
Taotao HUL
;
Zheng SONG
;
Jing MA
- Publication Type:Journal Article
- Keywords:
fluoxetine;
hERG;
patch clamp techniques;
whole-cell recording
- From:
Chinese Journal of Pharmacology and Toxicology
2014;(6):844-849
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTlVE To investigate the action mechanism of antidepressant fluoxetine on hERG ( ether-a-go-go-related gene ) potassium channel, and the effect of protein kinase C ( PKC ) agonist phorbol-12-myristate-13-acetate ( PMA) on fluoxetine inhibition. METHODS The whole cell patch clamp technique was used to record the change in hERG potassium current ( IKr ) on HEK293 cells that stably expressed hERG potassium channel ( hERG-HEK293 steady-state cells) , which was treated with fluoxe-tine 0.01, 0.1, 1 and 10μmol·L-1 , to study the concentration-and voltage-dependence of the effects on IKr, and to observe the changes in activation, inactivation and recovery dynamics of hERG potassium channel treated with fluoxetine 1μmol·L-1 . On this basis, the effect of PMA of 1μmol·L-1 on inhibition of fluoxetine 1 μmol·L-1 was explored. RESULTS Fluoxetine 0.01, 0.1, 1 and 10 μmol·L-1 inhibited IKr on hERG-HEK293 steady-state cells in a concentration- and voltage-dependent manner. The half maximal inhibitory concentration ( lC50 ) was about 0. 8 mmol·L-1 , and the Hill coefficient was about 1. 1. Fluoxetine 1 μmol·L-1 could reduce the activation, deactivation and recovery currents of IKr and affect the activation and recovery of hERG potassium channel. After fluoxetine inhibition of IKr became stable, PMA 1 μmol·L-1 could inhibit the blocking effect of fluoxetine on hERG potassium channels. CONCLUSlON Fluoxetine has obvious inhibitory effect on IKr of hERG-HEK293 steady-state cells, but the effect could be inhibited by PKC agonist PMA.
