Institute of Pharmacology, Medical Faculty, Johannes Kepler University Linz, 4020 Linz, Austria.
Walther Straub Institute of Pharmacology and Toxicology, Medical Faculty, Ludwig Maximilians University Munich, 80336 Munich, Germany.
Cells. 2022 Apr 26;11(9):1465. doi: 10.3390/cells11091465.
Two-pore channels (TPCs) are ligand-gated cation-selective ion channels that are preserved in plant and animal cells. In the latter, TPCs are located in membranes of acidic organelles, such as endosomes, lysosomes, and endolysosomes. Here, we focus on the function of these unique ion channels in mast cells, which are leukocytes that mature from myeloid hematopoietic stem cells. The cytoplasm of these innate immune cells contains a large number of granules that comprise messenger substances, such as histamine and heparin. Mast cells, along with basophil granulocytes, play an essential role in anaphylaxis and allergic reactions by releasing inflammatory mediators. Signaling in mast cells is mainly regulated via the release of Ca from the endoplasmic reticulum as well as from acidic compartments, such as endolysosomes. For the crosstalk of these organelles TPCs seem essential. Allergic reactions and anaphylaxis were previously shown to be associated with the endolysosomal two-pore channel TPC1. The release of histamine, controlled by intracellular Ca signals, was increased upon genetic or pharmacologic TPC1 inhibition. Conversely, stimulation of TPC channel activity by one of its endogenous ligands, namely nicotinic adenine dinucleotide phosphate (NAADP) or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P), were found to trigger the release of Ca from the endolysosomes; thereby improving the effect of TPC1 on regulated mast cell degranulation. In this review we discuss the importance of TPC1 for regulating Ca homeostasis in mast cells and the overall potential of TPC1 as a pharmacological target in anti-inflammatory therapy.
双孔通道（TPCs）是配体门控的阳离子选择性离子通道，存在于植物和动物细胞中。在后者中，TPCs 位于内体、溶酶体和内溶酶体等酸性细胞器的膜上。在这里，我们重点介绍这些独特的离子通道在肥大细胞中的功能，肥大细胞是从骨髓造血干细胞成熟的白细胞。这些先天免疫细胞的细胞质中含有大量包含信使物质（如组胺和肝素）的颗粒。肥大细胞与嗜碱性粒细胞一起，通过释放炎症介质，在过敏反应和过敏反应中发挥重要作用。肥大细胞中的信号主要通过内质网和酸性隔室（如内溶酶体）中 Ca 的释放来调节。对于这些细胞器的串扰，TPC 似乎是必不可少的。先前的研究表明，过敏反应和过敏反应与内溶酶体双孔通道 TPC1 有关。通过遗传或药理学抑制 TPC1，可增加由细胞内 Ca 信号控制的组胺释放。相反，其内源性配体烟碱腺嘌呤二核苷酸磷酸（NAADP）或磷脂酰肌醇 3,5-二磷酸（PI（3,5）P）之一刺激 TPC 通道活性，被发现可引发内溶酶体中 Ca 的释放；从而提高 TPC1 对调节性肥大细胞脱粒的作用。在这篇综述中，我们讨论了 TPC1 对调节肥大细胞 Ca 动态平衡的重要性以及 TPC1 作为抗炎治疗中药理学靶点的整体潜力。
