PT  - JOURNAL ARTICLE
AU  - Ping Li
AU  - Xueqin Chen
AU  - Qiansen Zhang
AU  - Yueming Zheng
AU  - Hualiang Jiang
AU  - Huaiyu Yang
AU  - Zhaobing Gao
TI  - The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels
AID  - 10.1124/jpet.114.217703
DP  - 2014 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 596--604
VI  - 351
IP  - 3
4099  - http://jpet.aspetjournals.org/content/351/3/596.short
4100  - http://jpet.aspetjournals.org/content/351/3/596.full
SO  - J Pharmacol Exp Ther2014 Dec 01; 351
AB  - Human ether-a-go-go–related gene (hERG) and KCNQ channels are two classes of voltage-gated potassium channels. Specific mutations have been identified that are causal for type II long QT (LQT2) syndrome, neonatal epilepsy, and benign familial neonatal convulsions. Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigating and treating the two diseases is likely more effective. In the current study, we found that NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea], a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4, and KCNQ2/Q3 channels, but not the cardiac KCNQ1. The effects of NS1643 on the KCNQ2 channel include left shifting of voltage for reaching 50% of the maximum conductance and slowing of deactivation. Analysis of the dose-response curve of NS1643 revealed an EC50 value of 2.44 ± 0.25 μM. A hydrophobic phenylalanine (F137) located at the middle region of the voltage-sensing domain was identified as critical for NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.