TRPM2 cation channels, oxidative stress and neurological diseases: where are we now?

Area of Science:

• Neuroscience
• Molecular Biology
• Ion Channels

Background:

• Transient Receptor Potential Melastatin 2 (TRPM2) channels are Na+ and Ca(2+)-permeable ion channels.
• TRPM2 channels are implicated in neuronal function and dysfunction, particularly in response to oxidative stress.
• TRPM2's role in the central nervous system (CNS) is increasingly recognized in various disease states.

Purpose of the Study:

• To summarize current understanding of TRPM2 channel gating mechanisms in neuronal cells.
• To review recent advances in TRPM2 channel function related to calcium (Ca2+) influx.
• To explore the involvement of TRPM2 in CNS diseases and the effects of potential blockers.

Main Methods:

• Literature review of previous findings and recent advances on TRPM2 channel function.
• Analysis of studies investigating TRPM2 channel gating by ADP-ribose (ADPR) and hydrogen peroxide (H2O2).
• Examination of experimental data on TRPM2 channel blockers in different neuronal cell types.

Main Results:

• TRPM2 channels can be gated by ADPR (with Ca2+) or H2O2, which binds to the Nudix domain.
• TRPM2 activation is linked to oxidative stress, inflammation, and neuronal cell death, notably in the striatum.
• Genetic variants in TRPM2 are associated with neurodegenerative diseases like ALS and Parkinsonism-dementia complex.
• TRPM2 contributes to secondary injury mechanisms in traumatic brain injury (TBI).
• TRPM2 channel blockers exhibit cell-specific efficacy; some blockers are ineffective in certain neuronal preparations.

Conclusions:

• TRPM2 channels in neurons are activated by both ADPR and H2O2, suggesting distinct or overlapping signaling pathways.
• The precise relationship between TRPM2 channel activation and neuronal cell death requires further elucidation.
• Further research into TRPM2 channel blockers is needed due to observed cell-specific effects.