Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P₂. Five things to know

Area of Science:

• Molecular biology
• Cellular physiology
• Ion channel research

Background:

• Two-pore channels (TPCs) are ancient voltage-gated ion channels.
• TPCs are primarily located on acidic organelles like endosomes and lysosomes.
• Understanding TPC activation mechanisms is crucial for cellular signaling research.

Purpose of the Study:

• To review recent advances in TPC activation by ligands.
• To elucidate the distinct gating mechanisms and ion selectivity of TPCs.
• To highlight the dynamic nature of TPC function in response to different agonists.

Main Methods:

• Literature review of recent studies on TPCs.
• Analysis of TPC gating by nicotinic acid adenine dinucleotide phosphate (NAADP).
• Investigation of TPC gating by phosphoinositide PI(3,5)P2.

Main Results:

• TPCs function as Ca2+-permeable, non-selective cation channels gated by NAADP indirectly via associated receptors.
• TPCs also act as Na+-selective channels directly gated by PI(3,5)P2, with a structurally resolved binding site.
• TPCs exhibit agonist-dependent switching of ion selectivity.

Conclusions:

• TPCs are versatile ion channels with dual gating mechanisms and dynamic ion selectivity.
• NAADP and PI(3,5)P2 represent distinct modes of TPC activation, influencing cellular calcium and sodium homeostasis.
• Further research into TPC function can reveal novel therapeutic targets for organelle-related diseases.