scholarly journals Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

2019 ◽  
Author(s):  
Ying Yin ◽  
Mengyu Wu ◽  
Allen L. Hsu ◽  
William F. Borschel ◽  
Mario J. Borgnia ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cell Types ◽  
Structural Transitions ◽  
Cryo Electron Microscopy ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Ligand Free ◽  
Transient Receptor ◽  
Open States

AbstractThe calcium-permeable transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types 1–3. Channel activation requires binding of both ADP-ribose (ADPR) 2,4–6 and Ca2+ 7. The recently published TRPM2 structures from Danio rerio in the ligand-free and in the ADPR/Ca2+-bound conditions represent the channel in closed and open states, which uncover substantial tertiary and quaternary conformational rearrangements 8. However, it is unclear how these rearrangements occur within the tetrameric channel during channel gating. Here we report two cryo-electron microscopy structures of TRPM2 from the same species in complex with Ca2+ alone, and with both ADPR and Ca2+, determined to an overall resolution of ~3.8 Å and ~4.2 Å respectively. In comparison with the published results, our studies capture TRPM2 in two-fold symmetric intermediate states, offering a glimpse of the structural transitions within the tetramer that bridge the closed and open conformations.

scholarly journals Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimer’s Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Jing Wang ◽  
Michael F. Jackson ◽  
Yu-Feng Xie
Keyword(s):  
Oxidative Stress ◽  
Synaptic Plasticity ◽  
Glial Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Synaptic Efficacy ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Trpm2 Channels ◽  
Transient Receptor

Synaptic plasticity refers to the ability of neurons to strengthen or weaken synaptic efficacy in response to activity and is the basis for learning and memory. Glial cells communicate with neurons and in this way contribute in part to plasticity in the CNS and to the pathology of Alzheimer’s disease (AD), a neurodegenerative disease in which impaired synaptic plasticity is causally implicated. The transient receptor potential melastatin member 2 (TRPM2) channel is a nonselective Ca2+-permeable channel expressed in both glial cells (microglia and astrocytes) and neurons. Recent studies indicated that TRPM2 regulates synaptic plasticity as well as the activation of glial cells. TRPM2 also modulates oxidative stress and inflammation through interaction with glial cells. As both oxidative stress and inflammation have been implicated in AD pathology, this suggests a possible contribution of TRPM2 to disease processes. Through modulating the homeostasis of glutathione, TRPM2 is involved in the process of aging which is a risk factor of AD. These results potentially point TRPM2 channel to be involved in AD through glial cells. This review summarizes recent advances in studying the contribution of TRPM2 in health and in AD pathology, with a focus on contributions via glia cells.

scholarly journals Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2′-phosphate

2015 ◽  
Vol 145 (5) ◽  
pp. 419-430 ◽  
Author(s):  
Balázs Tóth ◽  
Iordan Iordanov ◽  
László Csanády
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Biological Interest ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
First Time

Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel implicated in postischemic neuronal cell death, leukocyte activation, and insulin secretion, is activated by intracellular ADP ribose (ADPR). In addition, the pyridine dinucleotides nicotinamide-adenine-dinucleotide (NAD), nicotinic acid–adenine-dinucleotide (NAAD), and NAAD-2′-phosphate (NAADP) have been shown to activate TRPM2, or to enhance its activation by ADPR, when dialyzed into cells. The precise subset of nucleotides that act directly on the TRPM2 protein, however, is unknown. Here, we use a heterologously expressed, affinity-purified–specific ADPR hydrolase to purify commercial preparations of pyridine dinucleotides from substantial contaminations by ADPR or ADPR-2′-phosphate (ADPRP). Direct application of purified NAD, NAAD, or NAADP to the cytosolic face of TRPM2 channels in inside-out patches demonstrated that none of them stimulates gating, or affects channel activation by ADPR, indicating that none of these dinucleotides directly binds to TRPM2. Instead, our experiments identify for the first time ADPRP as a true direct TRPM2 agonist of potential biological interest.

Abstract P153: Crosstalk Between Vascular Redox and Calcium Signalling in Hypertension Involves Transient Receptor Potential Melastatin 2 (TRPM2) Channel

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Rhéure Alves-Lopes ◽  
Karla B Neves ◽  
Aikaterini Anagnostopoulou ◽  
Silvia Lacchini ◽  
Augusto C Montezano ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Signalling ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Transient Receptor

Regulation of calcium signalling by adenine-based second messengers

2007 ◽  
Vol 35 (1) ◽  
pp. 109-114 ◽  
Author(s):  
R. Fliegert ◽  
A. Gasser ◽  
A.H. Guse
Keyword(s):  
Transient Receptor Potential ◽  
Second Messengers ◽  
Calcium Signalling ◽  
Receptor Potential ◽  
Cell Types ◽  
Cellular Systems ◽  
Membrane Receptors ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Plasma Membrane Receptors

cADPR [cyclic ADPR (ADP-ribose)], NAADP (nicotinic acid–adenine dinucleotide phosphate) and ADPR belong to the family of adenine-containing second messengers. They are metabolically related and are all involved in the regulation of cellular Ca2+ homoeostasis. Activation of specific plasma membrane receptors is connected to cADPR formation in many cell types and tissues. In contrast receptor-mediated formation of NAADP and ADPR has been shown only in a few selected cellular systems. The intracellular Ca2+ channel triggered by cADPR is the RyR (ryanodine receptor); in the case of NAADP, both activation of RyR and a novel Ca2+ channel have been proposed. In contrast, ADPR opens the non-specific cation channel TRPM2 [TRP (transient receptor potential) melastatin 2] that belongs to the TRP family of ion channels.

scholarly journals A key role for Mg2+ in TRPM7's control of ROS levels during cell stress

2012 ◽  
Vol 445 (3) ◽  
pp. 441-448 ◽  
Author(s):  
Hsiang-Chin Chen ◽  
Li-Ting Su ◽  
Omayra González-Pagán ◽  
Jeffrey D. Overton ◽  
Loren W. Runnels
Keyword(s):  
Cell Survival ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cell Types ◽  
Cell Stress ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Dependent Manner ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The TRPM7 (transient receptor potential melastatin 7) channel has been shown to play a pivotal role in cell survival during brain ischaemia as well as in the survival of other cell types challenged with apoptotic stimuli. Ca2+ is thought to be central to the channel's ability to regulate ROS (reactive oxygen species) production. However, channel-mediated entry of Mg2+ and Zn2+ have also been implicated in cell death. In the present study, we show that depletion of TRPM7 by RNA interference in fibroblasts increases cell resistance to apoptotic stimuli by decreasing ROS levels in an Mg2+-dependent manner. Depletion of TRPM7 lowered cellular Mg2+, decreased the concentration of ROS and lessened p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) activation as well as decreased caspase 3 activation and PARP [poly(ADP-ribose) polymerase] cleavage in response to apoptotic stimuli. Re-expression of TRPM7 or of a kinase-inactive mutant of TRPM7 in TRPM7-knockdown cells increased cellular Mg2+ and ROS levels, as did expression of the Mg2+ transporter SLC41A2 (solute carrier family 41 member 2). In addition, expression of SLC41A2 increased the sensitivity of TRPM7-knockdown cells to apoptotic stimuli and boosted ROS generation in response to cell stress. Taken together, these data uncover an essential role for Mg2+ in TRPM7's control of cell survival and in the regulation of cellular ROS levels.

scholarly journals Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death

2020 ◽  
Vol 21 (17) ◽  
pp. 6026 ◽  
Author(s):  
Dae Ki Hong ◽  
A Ra Kho ◽  
Song Hee Lee ◽  
Jeong Hyun Jeong ◽  
Beom Seok Kang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
High Sensitivity ◽  
Synaptic Cleft ◽  
Global Cerebral Ischemia ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Transient Receptor

A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.

scholarly journals Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2

2017 ◽  
Vol 149 (2) ◽  
pp. 219-235 ◽  
Author(s):  
Peilin Yu ◽  
Xiwen Xue ◽  
Jianmin Zhang ◽  
Xupang Hu ◽  
Yan Wu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Structural Model ◽  
Receptor Potential ◽  
Adenosine Diphosphate ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Structure Based Drug Design ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Transient Receptor

Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel.

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