scholarly journals Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Zhe Zhang ◽  
Balázs Tóth ◽  
Andras Szollosi ◽  
Jue Chen ◽  
László Csanády
Keyword(s):  
Cell Activation ◽  
Transient Receptor Potential ◽  
Immune Cell ◽  
Phosphatidyl Inositol ◽  
Receptor Potential ◽  
Structural Features ◽  
Transient Receptor Potential Melastatin ◽  
Gating Mechanism ◽  
Trpm2 Channel ◽  
Transient Receptor

Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the ~3 Å resolution electron cryo-microscopic structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2.

scholarly journals Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 397
Author(s):  
Andras Szollosi
Keyword(s):  
Structure Function ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Immune Cell ◽  
Receptor Potential ◽  
Cation Channel ◽  
Biophysical Properties ◽  
Vast Number ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure–function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models.

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

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 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.

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