Anoctamins are a family of Ca2+-activated Cl- channels
Anoctamins are a family of Ca2+-activated Cl- channels
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DOI：
10.1242/jcs.109553
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Kunzelmann, Karl
中科院分区：
文献类型：
--
作者：
Tian, Yuemin;Schreiber, Rainer;Kunzelmann, Karl
Anoctamin 1（Ano1; TMEM16A）和Anoctamin 2（Ano2; TMEM16B）是通过细胞内Ca2+增加瞬时激活的新型Cl-通道。这些通道是上皮细胞分泌Cl 2、平滑肌细胞增殖和嗅觉信号转导所必需的.它们是遗传性疾病和癌症的核心，可以作为热传感器。令人惊讶的是，该蛋白质家族的另一个成员Ano6作为Ca2+激活的磷脂乱序酶起作用，其他蛋白质被报道为细胞内蛋白质。因此，目前尚不清楚anoctamins是否构成一个家族的钙激活的氯离子通道，或具有异质性功能的蛋白质。使用全细胞膜片钳技术，我们证明Ano4 - 10在HEK293细胞中表达时都能够产生瞬时Ca 2+激活的Cl-电流。尽管发现一些anoctamins（Ano 1、2、4、6、7）在质膜中良好表达，但其它ano（Ano 8、9、10）显示相当差的膜表达并且大部分保留在胞质溶胶中。Cl-电流的瞬时性质被证明是独立的细胞内Ca 2+水平。我们发现，失活的Ano1电流发生在持续存在的升高的Ca2+浓度，可能是钙调蛋白依赖性激酶。目前的研究结果表明，anoctamins是一个家庭的钙激活的氯离子通道，也诱导渗透性的阳离子。它们可以作为位于质膜或细胞内隔室中的Cl-通道起作用。这些结果增加了我们对anoctamins的生理意义及其在疾病中的作用的理解。
Anoctamin 1 (Ano1; TMEM16A) and anoctamin 2 (Ano2; TMEM16B) are novel Cl- channels transiently activated by an increase in intracellular Ca2+. These channels are essential for epithelial Cl 2 secretion, smooth muscle peristalsis and olfactory signal transduction. They are central to inherited diseases and cancer and can act as heat sensors. Surprisingly, another member of this protein family, Ano6, operates as a Ca2+-activated phospholipid scramblase, and others were reported as intracellular proteins. It is therefore unclear whether anoctamins constitute a family of Ca2+-activated Cl- channels, or are proteins with heterogeneous functions. Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca2+-activated Cl- currents when expressed in HEK293 cells. Although some anoctamins (Ano1, 2, 4, 6, 7) were found to be well expressed in the plasma membrane, others (Ano8, 9, 10) show rather poor membrane expression and were mostly retained in the cytosol. The transient nature of the Cl- currents was demonstrated to be independent of intracellular Ca2+ levels. We show that inactivation of Ano1 currents occurs in the continuous presence of elevated Ca2+ concentrations, possibly by calmodulin-dependent kinase. The present results demonstrate that anoctamins are a family of Ca2+-activated Cl- channels, which also induce permeability for cations. They may operate as Cl- channels located in the plasma membrane or in intracellular compartments. These results increase our understanding of the physiological significance of anoctamins and their role in disease.