Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

Area of Science:

• Cell Biology
• Molecular Biology
• Ion Channel Physiology

Background:

• Ion selectivity is a fundamental, typically immutable, characteristic of ion channels.
• The lysosomal ion channel TPC2's permeability and gating properties have been a subject of conflicting research.
• Understanding TPC2 function is crucial for lysosomal homeostasis and cellular signaling.

Purpose of the Study:

• To investigate the factors influencing the ion selectivity of the TPC2 channel.
• To resolve discrepancies in the reported properties of TPC2.
• To establish a new understanding of TPC2's functional plasticity.

Main Methods:

• High-throughput screening to identify TPC2 agonists.
• Electrophysiological recordings to assess ion currents (Ca2+ and Na+ selectivity).
• Site-directed mutagenesis to probe ligand-channel interactions.
• Measurements of lysosomal pH and exocytosis.

Main Results:

• Two distinct TPC2 agonists were identified, eliciting different ionic currents and Ca2+ signals.
• One agonist promoted non-selective cation currents, while the other induced Na+-selective currents.
• These distinct activities correlated with different activating messengers (NAADP vs. PI(3,5)P2) and affected lysosomal pH and exocytosis.

Conclusions:

• TPC2 ion selectivity is ligand-dependent, challenging the notion of immutability.
• A single TPC2 channel can mediate distinct ionic signatures based on the activating stimulus.
• This discovery provides a new paradigm for ion channel function and resolves previous controversies regarding TPC2.