scholarly journals Critical Intracellular Ca2+Dependence of Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel Activation

2003 ◽  
Vol 278 (13) ◽  
pp. 11002-11006 ◽  
Author(s):  
Damian McHugh ◽  
Richard Flemming ◽  
Shang-Zhong Xu ◽  
Anne-Laure Perraud ◽  
David J. Beech
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Channel Activation ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

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 The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Iordan Iordanov ◽  
Csaba Mihályi ◽  
Balázs Tóth ◽  
László Csanády
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Channel Gating ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chimeric Proteins ◽  
Transient Receptor Potential Melastatin ◽  
Biochemical Studies ◽  
Transient Receptor

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable cation channel essential for immunocyte activation, insulin secretion, and postischemic cell death. TRPM2 is activated by ADP ribose (ADPR) binding to its C-terminal cytosolic NUDT9-homology (NUDT9H) domain, homologous to the soluble mitochondrial ADPR pyrophosphatase (ADPRase) NUDT9. Reported ADPR hydrolysis classified TRPM2 as a channel-enzyme, but insolubility of isolated NUDT9H hampered further investigations. Here we developed a soluble NUDT9H model using chimeric proteins built from complementary polypeptide fragments of NUDT9H and NUDT9. When expressed in E.coli, chimeras containing up to ~90% NUDT9H sequence remained soluble and were affinity-purified. In ADPRase assays the conserved Nudix-box sequence of NUDT9 proved essential for activity (kcat~4-9s-1), that of NUDT9H did not support catalysis. Replacing NUDT9H in full-length TRPM2 with soluble chimeras retained ADPR-dependent channel gating (K1/2~1-5 μM), confirming functionality of chimeric domains. Thus, TRPM2 is not a 'chanzyme'. Chimeras provide convenient soluble NUDT9H models for structural/biochemical studies.

Abstract P219: Vascular Cross-talk Between Redox and Calcium Signaling in Hypertension Involves Transient Receptor Potential Melastatin 2 Channel Activation

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Rhéure Alves-Lopes ◽  
Augusto C Montezano ◽  
Karla B Neves ◽  
Aikaterini Anagnostopoulou ◽  
Silvia Lacchini ◽  
...  
Keyword(s):  
Cross Talk ◽  
Transient Receptor Potential ◽  
Vascular Dysfunction ◽  
Receptor Potential ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Channel Activation ◽  
Hypertensive Patients ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The transient receptor potential melastatin 2 cation channel (TRPM2) is redox-sensitive and promotes Ca 2+ influx after H 2 O 2 activation through oxidative modification and PARP-ADPR-dependent mechanisms. TRPM2 also regulates Na + influx, and by increasing [Na + ]i interferes with the Na + -Ca 2+ exchanger (NCX) inducing reverse mode action, promoting Ca 2+ influx. These processes may be driven by Nox4-derived H 2 O 2. We tested the hypothesis that vascular dysfunction in hypertension involves oxidative stress-induced TRPM2 activation through H 2 O 2 production, which in turn promotes Ca 2+ influx. Mesenteric arteries isolated from wildtype (WT), LinA3 (mice expressing human renin with Ang II-dependent hypertension), Nox4 -/- and LinA3/Nox4 -/- mice and vascular smooth muscle cells (VSMCs) from hypertensive and normotensive patients were used. Arteries from hypertensive LinA3 mice, exhibit increased U46619-induced vasoconstriction versus WT mice (Emax - LinA3 vs WT: 9.37 ± 0.51 vs 6.79 ± 0.29), an effect attenuated by olaparib (PARP-ADPR inhibitor) and 2-APB (TRPM2 blocker) and also increased mRNA expression (Fold change - related to control) of NOX4 (3.05 ± 0.30), TRPM2 (1.38 ± 0.24), NCX (1.973 ± 0.34) and salt inducible kinase 1 (1.833 ± 0.12) and sodium-potassium pump (1.43 ± 0.16), which are activated when intracellular levels of Na + rise beyond a critical point. These events seem to be regulated by NOX4, since they were not observed in mesenteric arteries from LinA3/Nox4 -/- mice. Ang II-induced Ca 2+ influx is potentiated in VSMCs from hypertensive patients (AUC-Ex490/Em535: normotensive: 15400±917.5 vs hypertensive - 22460±2388), a response followed by increased generation of O 2 - and H 2 O 2 in cells from hypertensive patients. These ROS effects were attenuated by catalase, and 2-APB, 8-br and olaparib (TRPM2 inhibitors) and benzamil, KB-R7943 and YM244769 (NCX inhibitors). Our data indicate that TRPM2 ion channel activation contributes to redox-sensitive vascular dysfunction in hypertension. These findings suggest that dysregulation of TRPM2-NOX4-derived ROS and NCX may contribute to redox- and Ca 2+ signalling important in vascular function in hypertension. TRPM2 may be a point of cross-talk between ROS and Ca 2+ signalling.

scholarly journals Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms

2020 ◽  
Author(s):  
Siyuan Zhao ◽  
Yevgen Yudin ◽  
Tibor Rohacs
Keyword(s):  
Intellectual Disability ◽  
Therapeutic Intervention ◽  
Room Temperature ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Transient Receptor Potential Melastatin ◽  
Heat Activation ◽  
Transient Receptor ◽  
Potential Therapeutic Intervention

ABSTRACTTransient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+ permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and CIM0216. TRPM3 mutations in humans were recently reported to be associated with intellectual disability and epilepsy; the functional effects of those mutations however were not reported. Here we show that both disease-associated mutations of TRPM3 render the channel overactive, but likely via different mechanisms. The Val to Met substitution in the S4-S5 loop induced a larger increase in basal activity and agonist sensitivity at room temperature than the Pro to Gln substitution in the extracellular segment of S6. In contrast, heat activation was increased more by the S6 mutant than by the S4-S5 segment mutant. Both mutants were inhibited by the TRPM3 antagonist primidone, suggesting a potential therapeutic intervention to treat this disease.

scholarly journals Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its α-kinase domain

2013 ◽  
Vol 25 (11) ◽  
pp. 2163-2175 ◽  
Author(s):  
Alvaro Yogi ◽  
Glaucia E. Callera ◽  
Sarah O'Connor ◽  
Tayze T. Antunes ◽  
William Valinsky ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cation Channel ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

scholarly journals Crosstalk Between Vascular Redox and Calcium Signaling in Hypertension Involves TRPM2 (Transient Receptor Potential Melastatin 2) Cation Channel

Hypertension ◽  
2020 ◽  
Vol 75 (1) ◽  
pp. 139-149 ◽  
Author(s):  
Rhéure Alves-Lopes ◽  
Karla B. Neves ◽  
Aikaterini Anagnostopoulou ◽  
Francisco J. Rios ◽  
Silvia Lacchini ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor
Sign in / Sign up

Export Citation Format

Share Document