The Mechanism of Calcium-Activated Chloride ANO6 Channel Inhibition by CaCCinh-A01

IF 1.1 Q4 CELL BIOLOGY

Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Pub Date : 2024-04-01 DOI:10.1134/S1990747824700041

D. O. Kolesnikov, E. R. Grigorieva, M. A. Nomerovskaya, D. S. Reshetin, A. V. Shalygin, E. V. Kaznacheyeva

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Abstract

Proteins of the anoctamine family (ANO) form calcium-activated chloride channels (CaCC) and phospholipid scramblases. The ANO6 (TMEM16F) protein, which combines the functions of a calcium-dependent scramblase and those of an ion channel, is considered as a molecular target for the treatment of blood clotting disorders, COVID-19-associated pneumonia, neurodegenerative diseases, and other pathologies. CaCCinh-A01, which is a channel blocker of the ANO family, is studied as a potential pharmacological drug. Previously, the effect of this inhibitor was studied using methods representing the integral ion current through the membrane, which does not allow the properties of single channels to be distinguished. Therefore, it remains unknown which characteristics of single channels are sensitive to the blocker: the channel open probability, the current amplitude, or the dwelling time of the channel open state. By registration of single ANO6 channels in HEK293 cells, we showed that the action of the inhibitor is due to a decrease in both the current amplitude and the dwelling time of the single ANO6 channels open state, which, in turn, leads to a decrease in their open state probability. Thus, we have characterized the mechanism of current reduction through ANO6 channels by the inhibitor CaCCinh A01.

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CaCCinh-A01 抑制钙激活氯化物 ANO6 通道的机制

摘要八胺家族（ANO）蛋白可形成钙激活氯离子通道（CaCC）和磷脂扰乱酶。ANO6 (TMEM16F)蛋白兼具钙依赖性扰乱酶和离子通道的功能，被认为是治疗凝血障碍、COVID-19相关肺炎、神经退行性疾病和其他病症的分子靶标。CaCCinh-A01是一种ANO家族的通道阻断剂，被作为一种潜在的药理学药物进行研究。以前，研究这种抑制剂的效果时使用的是代表通过膜的整体离子电流的方法，这种方法无法区分单一通道的特性。因此，单一通道的哪些特性对阻断剂敏感：通道开放概率、电流振幅或通道开放状态的停留时间，仍是未知数。通过对 HEK293 细胞中的单 ANO6 通道进行登记，我们发现抑制剂的作用是由于单 ANO6 通道开放状态的电流振幅和停留时间的降低，这反过来又导致其开放状态概率的降低。因此，我们描述了抑制剂 CaCCinh A01 通过 ANO6 通道降低电流的机制。

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来源期刊

Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology CELL BIOLOGY-

CiteScore

1.40

自引率

0.00%

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期刊介绍： Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology is an international peer reviewed journal that publishes original articles on physical, chemical, and molecular mechanisms that underlie basic properties of biological membranes and mediate membrane-related cellular functions. The primary topics of the journal are membrane structure, mechanisms of membrane transport, bioenergetics and photobiology, intracellular signaling as well as membrane aspects of cell biology, immunology, and medicine. The journal is multidisciplinary and gives preference to those articles that employ a variety of experimental approaches, basically in biophysics but also in biochemistry, cytology, and molecular biology. The journal publishes articles that strive for unveiling membrane and cellular functions through innovative theoretical models and computer simulations.