Discovery Of Novel Regulators Of TMEM16A Channel And The Physiological Effects Of The Regulators

Calcium activated chloride channels(CaCCs)are widely distributed in various tissues of vertebrates and non-vertebrates.They participate in many important physiological processes and are closely related to many diseases.Since 2008,TMEM16A,the molecular basis of CaCCs,was found to be an important drug target for the treatment of diseases related to CaCCs,the screening of its regulators has become a hot topic of this field.However,very few regulators for TMEM16A have been found till now and most of them are cell-damage compounds.Considering that traditional Chinese medicine has many advantages including rich contents,minor side effects,incomparable thousands of practice experience and most of them are natural products,this article mainly expounds the selection of specific regulators of TMEM16A from traditional Chinese medicine extracts,and investigates the mechanisms,physiological and pathological effects.With the help of the ion channel targeted drug screening technology system which had been explored and improved by our research group for many years,the author selected two TMEM16A channel modulators,Ginkgolide C and Silybin,through fluorescence microscopy and patch clamp technology.In addition,the effects and mechanisms of them were researched through the experimental methods at the cellular and tissue level,and the following conclusions were obtained:(1)Ginkgolide C and Silybin were found to be potentiator and inhibitor of TMEM16A channel respectively from 32 natural small molecule compounds;(2)Ginkgolide C indirectly activated TMEM16A channel by increasing intracellular calcium ion concentration.Ginkgolide C could stimulate ileal muscle contraction in guinea pigs by activating TMEM16A channel,and it was expected to provide basic research for the new strategy of prevention and treatment of intestinal peristalsis dysfunction;(3)Silybin could bind to TMEM16A channel directly and inhibited its activity.The IC₅₀ value of Silybin is 30.90±2.10?M.Further results showed that Silybin could inhibit the proliferation and migration of lung adenocarcinoma cells by inhibiting the activity of TMEM16A channel,which indicated that Silybin had the potential to provide basic research for new strategies of prevention and treatment of lung adenocarcinoma.