ArticleProceedings of the National Academy of Sciences of the United States of America2014
Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 41 citations in OpenAlex.
- Functional characterisation ofThe European respiratory journal · 2026Article
- Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution.Nature structural & molecular biology · 2024Article
- Functions of TRPs in retinal tissue in physiological and pathological conditions.Frontiers in molecular neuroscience · 2024Review
- Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation.International journal of molecular sciences · 2023Review
- TRPM2: bridging calcium and ROS signaling pathways-implications for human diseases.Frontiers in physiology · 2023Review
- Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Role of TRP ion channels in cerebral circulation and neurovascular communication.Neuroscience letters · 2021Review
- TRPM2 ion channels steer neutrophils towards a source of hydrogen peroxide.Scientific reports · 2021Article
- Species-Specific Regulation of TRPM2 by PI(4,5)PInternational journal of molecular sciences · 2021Article
- Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel.Life (Basel, Switzerland) · 2021Review
- Roles of NADMolecules (Basel, Switzerland) · 2020Review
- Structure-Function Relationship of TRPM2: Recent Advances, Contradictions, and Open Questions.International journal of molecular sciences · 2020Review
- The N-terminal domain in TRPM2 channel is a conserved nucleotide binding site.The Journal of general physiology · 2020Article
- A structural overview of the ion channels of the TRPM family.Cell calcium · 2020Review
- Synthesis of phosphonoacetate analogues of the second messenger adenosine 5'-diphosphate ribose (ADPR).RSC advances · 2020Article
- TRP ion channels: Proteins with conformational flexibility.Channels (Austin, Tex.) · 2019Review
- Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.eLife · 2019Article
- Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2.The Journal of organic chemistry · 2019Article
- Article
- Different substrate specificities of the two ADPR binding sites in TRPM2 channels of Nematostella vectensis and the role of IDPR.Scientific reports · 2019Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable cation channel expressed in immune cells of phagocytic lineage, pancreatic β cells, and brain neurons and is activated under oxidative stress. TRPM2 activity is required for immune cell activation and insulin secretion and is responsible for postischemic neuronal cell death. TRPM2 is opened by binding of ADP ribose (ADPR) to its C-terminal cytosolic nudix-type motif 9 (NUDT9)-homology (NUDT9-H) domain, which, when expressed in isolation, cleaves ADPR into AMP and ribose-5-phosphate. A suggested coupling of this enzymatic activity to channel gating implied a potentially irreversible gating cycle, which is a unique feature of a small group of channel enzymes known to date. The significance of such a coupling lies in the conceptually distinct pharmacologic strategies for modulating the open probability of channels obeying equilibrium versus nonequilibrium gating mechanisms. Here we examine the potential coupling of TRPM2 enzymatic activity to pore gating. Mutation of several residues proposed to enhance or eliminate NUDT9-H catalytic activity all failed to affect channel gating kinetics. An ADPR analog, α-β-methylene-ADPR (AMPCPR), was shown to be entirely resistant to hydrolysis by NUDT9, but nevertheless supported TRPM2 channel gating, albeit with reduced apparent affinity. The rate of channel deactivation was not slowed but, rather, accelerated in AMPCPR. These findings, as well as detailed analyses of steady-state gating kinetics of single channels recorded in the presence of a range of concentrations of ADPR or AMPCPR, identify TRPM2 as a simple ligand-gated channel that obeys an equilibrium gating mechanism uncoupled from its enzymatic activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.