BACKGROUND: Guanfu base A (GFA) and Guanfu base G (GFG) are chemicals isolated from Aconitum coreanum. The potassium channel encoded by the human ether-a-go-go related gene (HERG) plays an important role in repolarization of the cardiac action potential. The purpose of the present study was to investigate the effects of GFA and GFG on the HERG channel and its structure-function relationship. METHODS: The effects of GFA and GFG were investigated in human embryonic kidney 293 (HEK293) cells transiently transfected with HERG complementary DNA using a whole-cell patch clamp technique. RESULTS: GFA and GFG inhibited HERG channel current in concentration-, voltage-, and time-dependent manners. The IC50 for GFA and GFG was 1.64 mM and 17.9 μM, respectively. Both GFA and GFG shifted the activation curve in a negative direction and accelerated channel inactivation but showed no effect on the inactivation curve. Moreover, GFG also accelerated channel recovery from inactivation. CONCLUSIONS: Both GFA and GFG blocked HERG channel current. This effect was stronger after GFG treatment rather than GFA treatment. This blockade was dependent on open and inactivated channel states. These results indicate that GFA could be a rather promising antiarrhythmic drug without severe side effects, whereas GFG could cause QT prolongation and requires further research.
BACKGROUND: Guanfu base A (GFA) and Guanfu base G (GFG) are chemicals isolated from Aconitum coreanum. The potassium channel encoded by the human ether-a-go-go related gene (HERG) plays an important role in repolarization of the cardiac action potential. The purpose of the present study was to investigate the effects of GFA and GFG on the HERG channel and its structure-function relationship. METHODS: The effects of GFA and GFG were investigated in humanembryonic kidney 293 (HEK293) cells transiently transfected with HERG complementary DNA using a whole-cell patch clamp technique. RESULTS:GFA and GFG inhibited HERG channel current in concentration-, voltage-, and time-dependent manners. The IC50 for GFA and GFG was 1.64 mM and 17.9 μM, respectively. Both GFA and GFG shifted the activation curve in a negative direction and accelerated channel inactivation but showed no effect on the inactivation curve. Moreover, GFG also accelerated channel recovery from inactivation. CONCLUSIONS: Both GFA and GFG blocked HERG channel current. This effect was stronger after GFG treatment rather than GFA treatment. This blockade was dependent on open and inactivated channel states. These results indicate that GFA could be a rather promising antiarrhythmic drug without severe side effects, whereas GFG could cause QT prolongation and requires further research.
Authors: Kevin G M Kou; Jason J Pflueger; Toshihiro Kiho; Louis C Morrill; Ethan L Fisher; Kyle Clagg; Terry P Lebold; Jessica K Kisunzu; Richmond Sarpong Journal: J Am Chem Soc Date: 2018-06-19 Impact factor: 15.419