Modulation of Kv7 Channel Currents by Echinocystic Acid

Modulation of KCNQ-encoded voltage-gated potassium Kv7/M channel function represents an attractive strategy to treat neuronal excitability disorders such as epilepsy, pain, and depression. The Kv7 channel group includes five subfamily members (Kv7.1-Kv7.5). Pentacyclic triterpenes display extensive phar-macological activities including antitumor, anti-inflammatory, and antidepression effects. In this study, we investigated the ef-fects of pentacyclic triterpenes on Kv7 channels. Our results show that echinocystic acid, ursonic acid, oleanonic acid, demethylzey-lasteral, corosolic acid, betulinaldehyde, acetylursolic acid, and a-boswellic acid gradually exert decreasing degrees of Kv7.2/ Kv7.3 channel current inhibition. Echinocystic acid was the most potent inhibitor, with a half-maximal inhibitory concentration (IC50) of 2.5 mM. It significantly shifted the voltage-dependent activation curve in a positive direction and slowed the time constant of activation for Kv7.2/Kv7.3 channel currents. Furthermore, echino-cystic acid nonselectively inhibited Kv7.1-Kv7.5 channels. Taken together, our findings indicate that echinocystic acid is a novel and potent inhibitor that could be used as a tool to further under-stand the pharmacological functions of neuronal Kv7 channels. SIGNIFICANCE STATEMENT Pentacyclic triterpenes reportedly have multiple potential thera-peutic uses such as anticancer, anti-inflammatory, antioxidant, and antidepression effects. In the present study, we show that echinocystic acid, ursonic acid, oleanonic acid, and demethyl-zeylasteral inhibit Kv7.2/Kv7.3 channels to varying degrees. Of these, echinocystic acid was the most potent Kv7.2/Kv7.3 cur-rent inhibitor and inhibited Kv7.1-Kv7.5 currents in a nonselec-tive manner.

Automated summary

This study investigated the effects of pentacyclic triterpenes on Kv7 channels and found that echinocystic acid was the most potent inhibitor, which could be used to further understand the pharmacological functions of neuronal Kv7 channels.