Physiological Regulation and Pharmacology of Two-Pore Calcium Channels of the Endolysosomal System

Abstract— Two-pore calcium channels (TPCs) are localized in the membranes of endosomes and lysosomes and play a crucial role in the regulation of vesicular transport, autophagy, protein, nucleic acid, and lipid catabolism, recycling of plasma membrane receptors, and other processes occurring in the endolysosomal system. Humans express two types of channels, TPC1 and TPC2. Dysfunction of these channels is the cause of severe pathologies, including cancer and neurodegenerative diseases. Understanding the mechanisms of TPC channel regulation and identifying pharmacological pathways to influence their activity are essential for developing new approaches to the prevention and treatment of these diseases. This review characterizes the properties of two-pore channels and describes their regulation by phosphatidylinositol-3,5-bisphosphate and NAADP (nicotinic acid adenine dinucleotide phosphate), changes in channel activity during cell starvation, as well as the effects on TPC channels exerted by sphingosine, protein kinases P38 and JNK, and regulatory proteins mTor, Rab7a, and Tmem63a. Information on the pharmacology of TPC channels is provided. Groups of NAADP receptor site antagonists and compounds acting directly on the channel protein are highlighted. Part of the review is devoted to the description of plant-derived channel regulators and their potential use as anticancer drugs.