Calcium-activated chloride channels（CaCCs） are the crucial regulators of transepithelial fluid secretion, smooth muscle contraction and sensory transduction. Recently, compelling evidence has indicated that TMEM16A...Calcium-activated chloride channels（CaCCs） are the crucial regulators of transepithelial fluid secretion, smooth muscle contraction and sensory transduction. Recently, compelling evidence has indicated that TMEM16A（ANO1 or anoctamin-1） is a bona fide calcium-acvtivated chloride channel. A few small molecule CaCCs regulators are available for functional and therapeutic studies. We screened 126 natural compounds from Chinese herbs. Screening was performed with an iodide influx assay in Fischer rat thyroid epithelial cells to coexpress ANO1 and an iodide-sensitive fluorescent indicator（EYFP-H148Q/I152L）. Imperatorin, a coumarin compound, was identified to inhibit ANO1-mediated chloride transport activated by multiple calcium-elevating agonists. The inhibitory effect is dose-dependent with IC50～14.63 μmol/L. Interestingly, imperatorin activated CFTR chloride channel with EC50～35.52 μmol/L. The adverse effects of imperatorin on CaCC and CFTR chloride channels will make it useful in pharmacological dissection of chloride transport in airway and intestinal epithelium. Further studies are required to evaluate the therapeutic effects of imperatorin on hypertension, asthma and certain tumors.展开更多
Anoctamin 1(ANO1) or TMEM16 A gene encodes a member of Ca^(2+) activated Cl^(-) channels(CaCCs) that are critical for physiological functions,such as epithelial secretion,smooth muscle contraction and sensory signal t...Anoctamin 1(ANO1) or TMEM16 A gene encodes a member of Ca^(2+) activated Cl^(-) channels(CaCCs) that are critical for physiological functions,such as epithelial secretion,smooth muscle contraction and sensory signal transduction.The attraction and interest in ANO1/TMEM16 A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases,including asthma,neuropathic pain,hypertension and cancer.However,the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target.This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools,hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.展开更多
基金Supported by the National Natural Science Foundation of China(Nos.30670477, 30973577 and 30770493)the National Basic Research Program of China(No.2009CB521908)
文摘Calcium-activated chloride channels（CaCCs） are the crucial regulators of transepithelial fluid secretion, smooth muscle contraction and sensory transduction. Recently, compelling evidence has indicated that TMEM16A（ANO1 or anoctamin-1） is a bona fide calcium-acvtivated chloride channel. A few small molecule CaCCs regulators are available for functional and therapeutic studies. We screened 126 natural compounds from Chinese herbs. Screening was performed with an iodide influx assay in Fischer rat thyroid epithelial cells to coexpress ANO1 and an iodide-sensitive fluorescent indicator（EYFP-H148Q/I152L）. Imperatorin, a coumarin compound, was identified to inhibit ANO1-mediated chloride transport activated by multiple calcium-elevating agonists. The inhibitory effect is dose-dependent with IC50～14.63 μmol/L. Interestingly, imperatorin activated CFTR chloride channel with EC50～35.52 μmol/L. The adverse effects of imperatorin on CaCC and CFTR chloride channels will make it useful in pharmacological dissection of chloride transport in airway and intestinal epithelium. Further studies are required to evaluate the therapeutic effects of imperatorin on hypertension, asthma and certain tumors.
基金supported by grants from the National Natural Science foundation of China (81573410)the Ministry of Science and Technology of China (2018ZX09711001-004-006)+2 种基金Shandong Provincial Medicine and Health Technology Development Plan (2019WS145, China)Medical Research Guidance Plan of Qingdao Municipal Health Committee (2019-WJZD091, China)Qingdao Excellent Young Medical Talent Training Project。
文摘Anoctamin 1(ANO1) or TMEM16 A gene encodes a member of Ca^(2+) activated Cl^(-) channels(CaCCs) that are critical for physiological functions,such as epithelial secretion,smooth muscle contraction and sensory signal transduction.The attraction and interest in ANO1/TMEM16 A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases,including asthma,neuropathic pain,hypertension and cancer.However,the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target.This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools,hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.
