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

标题：TMEM16A抑制剂揭示TMEM16A是气道和肠上皮细胞中钙激活氯通道电导的组成部分

Authors: Won Namkung, Patricia W. Phuan, and Alan S. Verkman

作者: Won Namkung, Patricia W. Phuan, and Alan S. Verkman

Journal: Journal of Biological Chemistry

期刊: 《生物化学杂志》

Publication Date: January 21, 2011

发表日期: 2011年1月21日

Volume: 286

卷: 286

Issue: 3

期: 3

Pages: 2365-2374

页码: 2365-2374

DOI: 10.1074/jbc.M110.175109

Abstract

The study investigates the role of TMEM16A in calcium-activated chloride channels (CaCCs) in epithelial cells of the airway and intestine. Using specific TMEM16A inhibitors, the researchers found that TMEM16A contributes minimally to CaCC conductance in these cells. The findings suggest that other molecular entities are primarily responsible for CaCC activity in these tissues.

摘要

该研究调查了TMEM16A在气道和肠上皮细胞中钙激活氯通道（CaCC）中的作用。使用特定的TMEM16A抑制剂，研究人员发现TMEM16A对这些细胞中的CaCC导电贡献较小。研究结果表明，其他分子实体主要负责这些组织中的CaCC活性。

Introduction

Background: CaCCs play essential roles in various physiological processes including fluid secretion in epithelial tissues.

Objective: To determine the contribution of TMEM16A to CaCC activity using pharmacological inhibitors.

引言

• 背景: CaCC在包括上皮组织中的液体分泌在内的各种生理过程中起重要作用。
• 目标: 使用药理抑制剂确定TMEM16A对CaCC活性的贡献。

Methods

Inhibitors Used: Several small-molecule inhibitors specific to TMEM16A.

Experimental Models: Airway and intestinal epithelial cells.

Techniques: Patch-clamp electrophysiology to measure chloride currents, gene silencing, and pharmacological profiling.

方法

• 使用的抑制剂: 几种特定于TMEM16A的小分子抑制剂。
• 实验模型: 气道和肠上皮细胞。
• 技术: 用于测量氯电流的膜片钳电生理学、基因沉默和药理学分析。

Results

Key Findings:

- TMEM16A inhibitors significantly reduced CaCC currents, but only a minor portion of the total current was affected.

- Knockdown experiments confirmed that TMEM16A is not the major component of CaCC in these epithelial cells.

- The data imply the existence of other significant contributors to CaCC conductance.

结果

• 主要发现:
  • TMEM16A抑制剂显著降低了CaCC电流，但仅影响了总电流的一小部分。
  • 敲除实验证实，TMEM16A不是这些上皮细胞中CaCC的主要成分。
  • 数据表明存在其他显著贡献者。

Discussion

Implications: The study suggests revising the understanding of CaCC composition in epithelial tissues.

Future Directions: Identification and characterization of other molecular components of CaCCs.

讨论

• 影响: 该研究建议修订对上皮组织中CaCC组成的理解。
• 未来方向: 鉴定和表征CaCC的其他分子成分。

Conclusion

TMEM16A is a minor component of CaCCs in airway and intestinal epithelial cells, indicating the presence of other critical proteins in these channels.

结论

TMEM16A是气道和肠上皮细胞中CaCC的次要成分，表明这些通道中存在其他关键蛋白。

Compounds and Their CAS Numbers

1. **T16Ainh-A01**:

- **CAS Number**: 382180-17-8

- **Description**: A known inhibitor of TMEM16A, used in studies to explore its role in CaCC activity.

2. **Niflumic Acid**:

- **CAS Number**: 4394-00-7

- **Description**: A non-steroidal anti-inflammatory drug (NSAID) that acts as a TMEM16A inhibitor.

3. **Ani9**:

- **CAS Number**: Not readily available

- **Description**: A potent and selective TMEM16A inhibitor, often referenced in the literature but with limited availability in databases.