Wang Qiaochu, Zhu Michael X
Beijing Children's Hospital, Capital Medical University, Beijing, China.
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Handb Exp Pharmacol. 2023;278:35-56. doi: 10.1007/164_2022_606.
Two-pore channels, TPC1 and TPC2, are Ca- and Na-permeable cation channels expressed on the membranes of endosomes and lysosomes in nearly all mammalian cells. These channels have been implicated in Ca signaling initiated from the endolysosomes, vesicular trafficking, cellular metabolism, macropinocytosis, and viral infection. Although TPCs have been shown to mediate Ca release from acidic organelles in response to NAADP (nicotinic acid adenine dinucleotide phosphate), the most potent Ca mobilizing messenger, questions remain whether NAADP is a direct ligand of these channels. In whole-endolysosomal patch clamp recordings, it has been difficult to detect NAADP-evoked currents in vacuoles that expressed TPC1 or TPC2, while PI(3,5)P (phosphatidylinositol 3,5-bisphosphate) activated a highly Na-selective current under the same experimental configuration. In this chapter, we summarize recent progress in this area and provide our observations on NAADP-elicited TPC2 currents from enlarged endolysosomes as well as their possible relationships with the currents evoked by PI(3,5)P. We propose that TPCs are channels dually regulated by PI(3,5)P and NAADP in an interdependent manner and the two endogenous ligands may have both distinguished and cooperative roles.
双孔通道TPC1和TPC2是钙和钠通透的阳离子通道，几乎在所有哺乳动物细胞的内体和溶酶体膜上表达。这些通道与内溶酶体引发的钙信号传导、囊泡运输、细胞代谢、巨胞饮作用和病毒感染有关。尽管已证明TPCs可介导酸性细胞器响应NAADP（烟酰胺腺嘌呤二核苷酸磷酸）释放钙，NAADP是最有效的钙动员信使，但NAADP是否是这些通道的直接配体仍存在疑问。在全内溶酶体膜片钳记录中，在表达TPC1或TPC2的液泡中很难检测到NAADP诱发的电流，而在相同实验条件下，PI(3,5)P（磷脂酰肌醇3,5-二磷酸）激活了一种高度钠选择性电流。在本章中，我们总结了该领域的最新进展，并提供了我们对来自扩大的内溶酶体的NAADP诱发的TPC2电流的观察结果，以及它们与PI(3,5)P诱发的电流的可能关系。我们提出，TPCs是由PI(3,5)P和NAADP以相互依赖的方式双重调节的通道，这两种内源性配体可能具有不同但又协同的作用。
