TMEM16A Inhibitors Reveal TMEM16A as a Minor Component of Calcium-activated Chloride Channel Conductance in Airway and Intestinal Epithelial Cells

氯离子通道 硝氟酸 化学 囊性纤维化跨膜传导调节器 粘液 生物化学 细胞生物学 生物 生态学 有机化学 基因
作者
W. Namkung,Puay-Wah Phuan,A. S. Verkman
出处
期刊:Journal of Biological Chemistry [Elsevier BV]
卷期号:286 (3): 2365-2374 被引量:334
标识
DOI:10.1074/jbc.m110.175109
摘要

TMEM16A (ANO1) functions as a calcium-activated chloride channel (CaCC). We developed pharmacological tools to investigate the contribution of TMEM16A to CaCC conductance in human airway and intestinal epithelial cells. A screen of ∼110,000 compounds revealed four novel chemical classes of small molecule TMEM16A inhibitors that fully blocked TMEM16A chloride current with an IC50 < 10 μm, without interfering with calcium signaling. Following structure-activity analysis, the most potent inhibitor, an aminophenylthiazole (T16Ainh-A01), had an IC50 of ∼1 μm. Two distinct types of inhibitors were identified. Some compounds, such as tannic acid and the arylaminothiophene CaCCinh-A01, fully inhibited CaCC current in human bronchial and intestinal cells. Other compounds, including T16Ainh-A01 and digallic acid, inhibited total CaCC current in these cells poorly, but blocked mainly an initial, agonist-stimulated transient chloride current. TMEM16A RNAi knockdown also inhibited mainly the transient chloride current. In contrast to the airway and intestinal cells, all TMEM16A inhibitors fully blocked CaCC current in salivary gland cells. We conclude that TMEM16A carries nearly all CaCC current in salivary gland epithelium, but is a minor contributor to total CaCC current in airway and intestinal epithelia. The small molecule inhibitors identified here permit pharmacological dissection of TMEM16A/CaCC function and are potential development candidates for drug therapy of hypertension, pain, diarrhea, and excessive mucus production. TMEM16A (ANO1) functions as a calcium-activated chloride channel (CaCC). We developed pharmacological tools to investigate the contribution of TMEM16A to CaCC conductance in human airway and intestinal epithelial cells. A screen of ∼110,000 compounds revealed four novel chemical classes of small molecule TMEM16A inhibitors that fully blocked TMEM16A chloride current with an IC50 < 10 μm, without interfering with calcium signaling. Following structure-activity analysis, the most potent inhibitor, an aminophenylthiazole (T16Ainh-A01), had an IC50 of ∼1 μm. Two distinct types of inhibitors were identified. Some compounds, such as tannic acid and the arylaminothiophene CaCCinh-A01, fully inhibited CaCC current in human bronchial and intestinal cells. Other compounds, including T16Ainh-A01 and digallic acid, inhibited total CaCC current in these cells poorly, but blocked mainly an initial, agonist-stimulated transient chloride current. TMEM16A RNAi knockdown also inhibited mainly the transient chloride current. In contrast to the airway and intestinal cells, all TMEM16A inhibitors fully blocked CaCC current in salivary gland cells. We conclude that TMEM16A carries nearly all CaCC current in salivary gland epithelium, but is a minor contributor to total CaCC current in airway and intestinal epithelia. The small molecule inhibitors identified here permit pharmacological dissection of TMEM16A/CaCC function and are potential development candidates for drug therapy of hypertension, pain, diarrhea, and excessive mucus production.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
咖喱爆炒鱼蛋完成签到,获得积分20
刚刚
刚刚
刚刚
量子星尘发布了新的文献求助10
1秒前
zzz发布了新的文献求助50
1秒前
nihao发布了新的文献求助10
1秒前
沉默寻凝完成签到,获得积分10
1秒前
2秒前
豆芽完成签到,获得积分10
2秒前
meredith0571完成签到,获得积分10
2秒前
2秒前
深情安青应助黄紫红蓝采纳,获得10
2秒前
希望天下0贩的0应助一粟采纳,获得10
2秒前
露似珍珠月似弓完成签到,获得积分10
3秒前
缓慢钢笔发布了新的文献求助10
4秒前
nyq完成签到,获得积分10
4秒前
4秒前
4秒前
科研通AI2S应助NXK采纳,获得10
4秒前
4秒前
kekeke完成签到,获得积分10
4秒前
keyanzhang完成签到,获得积分10
5秒前
5秒前
6秒前
Quinna发布了新的文献求助10
6秒前
z1z1z发布了新的文献求助10
6秒前
cchi完成签到,获得积分10
6秒前
7秒前
自由沧海发布了新的文献求助10
7秒前
jing完成签到,获得积分10
7秒前
7秒前
浮游应助wangjiewen1109采纳,获得10
7秒前
群众完成签到,获得积分10
7秒前
Tomma完成签到,获得积分10
8秒前
kkm完成签到,获得积分10
8秒前
8秒前
8秒前
爆米花应助正无穷采纳,获得10
8秒前
小诗发布了新的文献求助10
8秒前
cxcx发布了新的文献求助10
8秒前
高分求助中
(应助此贴封号)【重要!!请各用户(尤其是新用户)详细阅读】【科研通的精品贴汇总】 10000
SOFT MATTER SERIES Volume 22 Soft Matter in Foods 1000
Zur lokalen Geoidbestimmung aus terrestrischen Messungen vertikaler Schweregradienten 1000
Storie e culture della televisione 500
Selected research on camelid physiology and nutrition 500
《2023南京市住宿行业发展报告》 500
Food Microbiology - An Introduction (5th Edition) 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 内科学 生物化学 物理 计算机科学 纳米技术 遗传学 基因 复合材料 化学工程 物理化学 病理 催化作用 免疫学 量子力学
热门帖子
关注 科研通微信公众号,转发送积分 4885652
求助须知:如何正确求助?哪些是违规求助? 4170459
关于积分的说明 12941799
捐赠科研通 3931212
什么是DOI,文献DOI怎么找? 2156914
邀请新用户注册赠送积分活动 1175326
关于科研通互助平台的介绍 1079935