Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2014 Nov 25;11147:16949-54. doi: 10.1073/pnas.1412449111.
Show Gene links
Show Anatomy links
Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating.
Tóth B
,
Iordanov I
,
Csanády L
.
???displayArticle.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.
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995, Pubmed
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995,
Pubmed
Chakrapani,
Gating dynamics of the acetylcholine receptor extracellular domain.
2004,
Pubmed
Csanády,
Rapid kinetic analysis of multichannel records by a simultaneous fit to all dwell-time histograms.
2000,
Pubmed
Csanády,
Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate.
2009,
Pubmed
,
Xenbase
Csanády,
Catalyst-like modulation of transition states for CFTR channel opening and closing: new stimulation strategy exploits nonequilibrium gating.
2014,
Pubmed
,
Xenbase
Csanády,
Strict coupling between CFTR's catalytic cycle and gating of its Cl- ion pore revealed by distributions of open channel burst durations.
2010,
Pubmed
,
Xenbase
Csanády,
Statistical evaluation of ion-channel gating models based on distributions of log-likelihood ratios.
2006,
Pubmed
Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed
Hermosura,
Altered functional properties of a TRPM2 variant in Guamanian ALS and PD.
2008,
Pubmed
Jiang,
Crystal structure and mechanism of a calcium-gated potassium channel.
2002,
Pubmed
Kühn,
Sites of the NUDT9-H domain critical for ADP-ribose activation of the cation channel TRPM2.
2004,
Pubmed
Liao,
Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
2013,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
McQuillin,
Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3.
2006,
Pubmed
Nilius,
Transient receptor potential cation channels in disease.
2007,
Pubmed
Perraud,
NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved mitochondrial ADP-ribose pyrophosphatase.
2003,
Pubmed
Perraud,
ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology.
2001,
Pubmed
Perraud,
Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels.
2005,
Pubmed
Ramjeesingh,
Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator).
1999,
Pubmed
Runnels,
TRP-PLIK, a bifunctional protein with kinase and ion channel activities.
2001,
Pubmed
Shen,
The crystal structure and mutational analysis of human NUDT9.
2003,
Pubmed
Tóth,
Pore collapse underlies irreversible inactivation of TRPM2 cation channel currents.
2012,
Pubmed
,
Xenbase
Tóth,
Identification of direct and indirect effectors of the transient receptor potential melastatin 2 (TRPM2) cation channel.
2010,
Pubmed
,
Xenbase
Uchida,
Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice.
2011,
Pubmed
Vergani,
On the mechanism of MgATP-dependent gating of CFTR Cl- channels.
2003,
Pubmed
,
Xenbase
Yamamoto,
TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration.
2008,
Pubmed
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
