Diversity of two-pore channels and the accessory NAADP receptors in intracellular Ca²⁺ signaling

Intracellular Ca²⁺ signaling via changes or oscillation in cytosolic Ca²⁺ concentration controls almost every aspect of cellular function and physiological processes, such as gene transcription, cell motility and proliferation, muscle contraction, and learning and memory. Two-pore channels (TPCs) are a class of eukaryotic cation channels involved in intracellular Ca²⁺ signaling, likely present in a multitude of organisms from unicellular organisms to mammals. Accumulated evidence indicates that TPCs play a critical role in Ca²⁺ mobilization from intracellular stores mediated by the second messenger molecule, nicotinic acid adenine dinucleotide phosphate (NAADP). In recent years, significant progress has been made regarding our understanding of the structures and function of TPCs, including Cryo–EM structure determination of mammalian TPCs and characterization of a plastid TPC in a single–celled parasite. The recent identification of Lsm12 and JPT2 as NAADP-binding proteins provides a new molecular basis for understanding NAADP-evoked Ca²⁺ signaling. In this review, we summarize basic structural and functional aspects of TPCs and highlight the most recent studies on the newly discovered TPC in a parasitic protozoan and the NAADP-binding proteins LSM12 and JPT2 as new key players in NAADP signaling.