TPCs: FROM PLANT TO HUMAN

Area of Science:

• Molecular Biology
• Cell Physiology
• Ion Channel Function

Background:

• Two-pore channels (TPCs) were initially identified in plants and later in mammals, with early studies debating their function as Ca²⁺ or Na⁺ channels.
• Conflicting findings regarding mammalian TPCs' activation by nicotinic acid adenine dinucleotide phosphate (NAADP) or phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] created a significant scientific dispute.
• TPCs are implicated in various cellular processes, including autophagy, exocytosis, endocytosis, and intracellular trafficking, with implications for diseases like fatty liver disease, infectious diseases, cancer, and neurodegenerative disorders.

Purpose of the Study:

• To reconcile the conflicting findings on mammalian TPC activation mechanisms and channel selectivity.
• To explore the role of TPCs in various physiological and pathophysiological processes, including lysosomal storage diseases.
• To review the latest advancements in TPC structure, function, and their potential as drug targets.

Main Methods:

• Utilized lipophilic small molecule agonists to mimic NAADP and PI(3,5)P2 activation modes of TPC2.
• Incorporated structural evidence to elucidate TPC2's ligand-dependent ion selectivity.
• Reviewed existing literature on TPC function, physiology, and pathophysiology, focusing on plant and mammalian systems.

Main Results:

• TPC2 exhibits ligand-dependent selectivity for Ca²⁺ versus Na⁺ (N-type vs. P-type activation), reconciling previous disputes.
• Discovery of NAADP-binding proteins (Jupiter microtubule-associated homolog 2 protein and Lsm12) supports the requirement of auxiliary proteins for NAADP activation.
• TPC dysfunction is linked to diverse pathologies, including impaired trafficking in fatty liver disease, infectious diseases (Ebola, COVID-19), cancer, and neurodegenerative lysosomal storage diseases, where P-type activation shows therapeutic promise.

Conclusions:

• The activation and function of TPCs are more complex than previously thought, involving ligand-dependent selectivity and auxiliary protein interactions.
• TPCs play critical roles in cellular homeostasis and are implicated in a wide spectrum of human diseases, underscoring their physiological significance.
• Targeting TPCs presents a promising therapeutic strategy for various conditions, including lysosomal storage diseases, infectious diseases, and cancer.