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Published on: October 4, 2019
TPCs: From plant to human
Yvonne Eileen Klingl1,2, Arnas Petrauskas1,2, Dawid Jaślan1
1Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
Physiological Reviews
|April 3, 2025
Summary
Two-pore channels (TPCs) are crucial for cellular calcium signaling and ion transport. Recent research reconciles TPC activation mechanisms and highlights their role in diseases, positioning them as potential drug targets.
Area of Science:
- Molecular Biology
- Cell Biology
- Physiology
Background:
- Two-pore channels (TPCs) were initially identified in plants and later in mammals, with early studies debating their function and activation mechanisms.
- Conflicting findings proposed TPCs as either NAADP-activated Ca2+ channels or PI(3,5)P2-activated Na+ channels.
Purpose of the Study:
- To reconcile the differing activation mechanisms of mammalian TPCs.
- To explore the physiological and pathophysiological roles of TPCs.
- To discuss TPCs as potential therapeutic targets.
Main Methods:
- Utilized lipophilic small molecule agonists to mimic TPC activation modes.
- Employed structural biology to elucidate ligand-dependent channel selectivity.
- Investigated the role of auxiliary proteins like JPT2 and Lsm12 in NAADP activation.
- Examined TPC function in cellular processes and disease models.
Main Results:
- TPC2 exhibits ligand-dependent selectivity for Ca2+ versus Na+ (N- vs. P-type activation).
- Discovery of NAADP-binding proteins (JPT2, Lsm12) supports NAADP activation hypothesis.
- TPC dysfunction is implicated in autophagy, trafficking, infectious diseases, cancer, and neurodegenerative disorders.
- P-type activation of TPC2 shows therapeutic potential in lysosomal storage disease models.
Conclusions:
- TPC activation mechanisms are reconciled, demonstrating ligand-dependent channel gating and selectivity.
- TPCs play significant roles in diverse physiological processes and diseases.
- TPCs represent promising drug targets for various pathological conditions.
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