Anoctamin家族中钙激活氯离子通道调节剂筛选及应用研究进展

Research progress in screening and applications of calciumactivated chloride ion channel modulators in Anoctamin family

钙激活氯离子通道(CaCC)是一类能通过胞内钙离子激活转运氯离子的通道蛋白,其主要在神经元和肌细胞中参与调节膜电位、细胞内钙平衡和细胞兴奋性等重要的生理作用。Anoctamin(Ano)家族中Ano1是最经典的CaCC,Ano1的靶向调节剂对癌症、囊性纤维化、高血压、腹泻和哮喘等疾病具有潜在治疗作用。自2008年Ano1首次被发现后,先后出现了多种CaCC特异性调节剂的筛选方法,主要包括基于荧光蛋白的高通量初级筛选、电生理膜片钳技术和虚拟筛选,进而发现了多种药理学作用不同的小分子调节剂。本文综述了目前较为主流的筛选方法的原理和优缺点,并对迄今发现的Ano1特异性调节剂的化学结构和潜在的应用进展进行综述。

Calcium-activated chloride channels(CaCCs)are a class of channel proteins that trans-port chloride ions activated by intracellular calcium,which play a crucial role in regulating membrane potential,intracellular calcium balance,and cell excitability,particularly in neurons and muscle cells.In the Anoctamin(Ano)family,Ano1 is the most classic CaCC.Targeted modulators of Ano1 have poten-tial therapeutic effects against such diseases as cancer,cystic fibrosis,hypertension,diarrhea,and asthma.Since the discovery of Ano1 in 2008,several methods for screening CaCC-specific modulators have emerged including high-throughput primary screening of fluorescent proteins,electrophysiological patch clamp technique and virtual screening,and identification of small molecule modulators with diverse pharmacological effects.This paper summarizes the principles,advantages and disadvantages of the mainstream screening methods,and reviews the chemical structures and potential applications of Ano1-specific modulators discovered to date.