Two-pore channels (TPCs): current controversies
Anthony J Morgan1, Antony Galione
1Department of Pharmacology, University of Oxford, Oxford, UK.
Abstract:
Much excitement surrounded the proposal that a family of endo-lysosomal channels, the two-pore channels (TPCs) were the long sought after targets of the Ca(2+) -mobilising messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, the role of TPCs in NAADP signalling may be more complex than originally envisaged. First, NAADP may not bind directly to TPCs but via an accessory protein. Second, two papers recently challenged the notion that TPCs are NAADP-regulated Ca(2+) channels by suggesting that they are highly selective Na(+) channels regulated by the lipid phosphatidylinositol 3,5-bisphosphate and by ATP. This paper aims critically to evaluate the evidence for TPCs as NAADP targets and to discuss how the new findings fit in with what we know about endo-lysosomal Ca(2+) stores.
Insights
Two-pore channels (TPCs) may not directly bind nicotinic acid adenine dinucleotide phosphate (NAADP). Emerging evidence suggests TPCs are sodium channels regulated by lipids and ATP, complicating their role in cellular calcium signaling.
Area of Science:
- Cell Biology
- Molecular Physiology
- Ion Channel Function
Background:
- Two-pore channels (TPCs) were proposed as targets for the calcium (Ca2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP).
- This hypothesis suggested TPCs mediate NAADP-dependent calcium release from endo-lysosomal stores.
Purpose of the Study:
- To critically evaluate the evidence linking TPCs to NAADP signaling.
- To discuss the implications of recent findings on TPC function within the context of endo-lysosomal calcium signaling.
Main Methods:
- Literature review and critical analysis of existing research on TPCs and NAADP.
- Comparison of proposed TPC functions with established models of endo-lysosomal calcium regulation.
Main Results:
- Evidence suggests NAADP may not directly bind TPCs, potentially requiring accessory proteins.
- Recent studies propose TPCs function as selective sodium (Na+) channels, regulated by phosphatidylinositol 3,5-bisphosphate and ATP, challenging their role as Ca2+ channels.
Conclusions:
- The role of TPCs in NAADP signaling is more complex than initially thought.
- Alternative mechanisms for TPC regulation and function, particularly as Na+ channels, need further investigation to understand their contribution to cellular calcium homeostasis.
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