TRPM2: a multifunctional ion channel for calcium signalling
Adriana Sumoza-Toledo1, Reinhold Penner
1Center for Biomedical Research, The Queen's Medical Center, University of Hawaii, 1301 Punchbowl Street - UHT 8, HI 96813, USA.
Abstract:
The transient potential receptor melastatin-2 (TRPM2) channel has emerged as an important Ca(2+) signalling mechanism in a variety of cells, contributing to cellular functions that include cytokine production, insulin release, cell motility and cell death. Its ability to respond to reactive oxygen species has made TRPM2 a potential therapeutic target for chronic inflammation, neurodegenerative diseases, and oxidative stress-related pathologies. TRPM2 is a non-selective, calcium (Ca(2+))-permeable cation channel of the melastatin-related transient receptor potential (TRPM) ion channel subfamily. It is activated by intracellular adenosine diphosphate ribose (ADPR) through a diphosphoribose hydrolase domain in its C-terminus and regulated through a variety of factors, including synergistic facilitation by [Ca(2+)](i), cyclic ADPR, H(2)O(2), NAADP, and negative feedback regulation by AMP and permeating protons (pH). In addition to its role mediating Ca(2+) influx into the cells, TRPM2 can also function as a lysosomal Ca(2+) release channel, contributing to cell death. The physiological and pathophysiological context of ROS-mediated events makes TRPM2 a promising target for the development of therapeutic tools of inflammatory and degenerative diseases.
Insights
Transient potential receptor melastatin-2 (TRPM2) channels are key calcium (Ca2+) signaling mechanisms involved in various cellular functions. Their role in reactive oxygen species (ROS) response makes TRPM2 a promising therapeutic target for inflammatory and neurodegenerative diseases.
Area of Science:
- Ion channel research
- Cellular signaling
- Molecular biology
Background:
- Transient potential receptor melastatin-2 (TRPM2) is a calcium (Ca2+)-permeable cation channel.
- TRPM2 plays a role in cellular functions like cytokine production, insulin release, cell motility, and cell death.
- Its sensitivity to reactive oxygen species (ROS) implicates it in oxidative stress-related pathologies.
Purpose of the Study:
- To elucidate the signaling mechanisms and regulatory factors of the TRPM2 channel.
- To highlight the therapeutic potential of TRPM2 for inflammatory and neurodegenerative diseases.
Main Methods:
- Analysis of TRPM2 channel structure and function.
- Investigation of TRPM2 activation by adenosine diphosphate ribose (ADPR).
- Examination of TRPM2 regulation by intracellular calcium ([Ca2+]i), cyclic ADPR, H2O2, NAADP, AMP, and protons (pH).
Main Results:
- TRPM2 is activated by intracellular ADPR via its C-terminal diphosphoribose hydrolase domain.
- TRPM2 activity is modulated by synergistic factors like [Ca2+]i, cyclic ADPR, H2O2, and NAADP.
- Negative feedback regulation occurs through AMP and permeating protons.
- TRPM2 functions in both Ca2+ influx and lysosomal Ca2+ release, contributing to cell death.
Conclusions:
- TRPM2 is a crucial Ca2+ signaling channel with diverse cellular roles.
- Its involvement in ROS-mediated events positions TRPM2 as a significant therapeutic target for oxidative stress, inflammation, and neurodegeneration.
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