Cell death modulation by transient receptor potential melastatin channels TRPM2 and TRPM7 and their underlying molecular mechanisms

2021 ◽  
pp. 114664
Author(s):  
Ruixue Shi ◽  
Yu Fu ◽  
Dongyi Zhao ◽  
Tomasz Boczek ◽  
Wuyang Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

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.

scholarly journals Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine

2008 ◽  
Vol 294 (6) ◽  
pp. R2001-R2007 ◽  
Author(s):  
Lusliany J. Rondón ◽  
Wouter M. Tiel Groenestege ◽  
Yves Rayssiguier ◽  
Andrzej Mazur
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
The Body ◽  
Deficient Diet ◽  
Adequate Diet ◽  
Low Magnesium ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
The Relationship

The body maintains Mg2+ homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg2+ transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg2+ transport in intestine and kidney. To define the relationship between Mg2+ status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg2+-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg2+ status. In addition, the mice were subjected to a severely Mg2+-deficient diet. Our results show that C57BL/6J mice fed a severely Mg2+-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg2+-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice. A severely Mg2+-deficient diet led to hypomagnesemia and hypomagnesuria in both strains. Furthermore, this diet induced kidney TRPM6 expression in MgL mice, but not in MgH mice. In conclusion, as shown in C57BL/6J mice, dietary Mg2+-restriction results in increased Mg2+ (re)absorption, which is correlated with increased TRPM6 expression. In MgL and MgH mice, the inherited Mg2+ status is linked to different TRPM6 expression. The MgL and MgH mice respond differently to a low-Mg2+ diet with regard to TRPM6 expression in the kidney, consistent with genetic factors contributing to the regulation of cellular Mg2+ levels. Further studies of these mice strains could improve our understanding of the genetics of Mg2+ homeostasis.

scholarly journals Farnesyl pyrophosphate is a new danger signal inducing acute cell death

PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001134
Author(s):  
Jing Chen ◽  
Xiaochen Zhang ◽  
Liping Li ◽  
Xianqiang Ma ◽  
Chunxiao Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Farnesyl Pyrophosphate ◽  
Danger Signal ◽  
Vital Event ◽  
Mva Pathway ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.

scholarly journals TRPM4 is required for calcium oscillations downstream from the stretch-activated TRPV4 channel

2021 ◽  
Author(s):  
Oleg Yarishkin ◽  
Tam T. Phuong ◽  
Felix Vazquez-Chona ◽  
Jacques A Bertrand ◽  
Sarah Redmon ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Membrane Surface ◽  
Receptor Potential ◽  
Calcium Oscillations ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Insight Into

Transduction of mechanical information is influenced by physical, chemical and thermal cues but the molecular mechanisms through which transducer activation shapes temporal signaling remain underexplored. In the present study, electrophysiology, histochemistry and functional imaging were combined with gene silencing and heterologous expression to gain insight into calcium signaling downstream from TRPV4 (Transient Receptor Potential Vanilloid 4), a stretch-activated nonselective cation channel. We show that trabecular meshwork (TM) cells, which employ mechanotransduction to actively regulate intraocular pressure, respond to the TRPV4 agonist GSK1016790A with fluctuations in intracellular Ca2+ concentration ([Ca2+]i) and an increase in [Na+]i. [Ca2+]i oscillations coincided with a monovalent cation current that was suppressed by BAPTA, Ruthenium Red and 9-phenanthrol, an inhibitor of TRPM4 (Transient Receptor Potential Melastatin 4) channels. Accordingly, TM cells expressed TRPM4 mRNA, protein at the expected 130-150 kDa and showed punctate TRPM4 immunoreactivity at the membrane surface. Genetic silencing of TRPM4 antagonized TRPV4-evoked oscillatory signaling whereas TRPV4 and TRPM4 co-expression in HEK-293 cells reconstituted the oscillations. Membrane potential recordings indicated that TRPM4-dependent oscillations required release of Ca2+ from internal stores. 9-phenanthrol did not affect the outflow facility in mouse eyes. Collectively, our results show that TRPV4 activity initiates dynamic calcium signaling in TM cells by stimulating TRPM4 channels and intracellular Ca2+ release. These findings provide insight into the complexity of membrane-cytosolic interactions during TRPV4 signaling and may foster strategies to promote homeostatic regulation and counter pathological remodeling within the conventional outflow pathway of the mammalian eye.

scholarly journals Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer

2008 ◽  
Vol 99 (12) ◽  
pp. 2502-2509 ◽  
Author(s):  
Byung Joo Kim ◽  
Eun Jung Park ◽  
Jae Hwa Lee ◽  
Ju-Hong Jeon ◽  
Seon Jeong Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

scholarly journals Transient receptor potential melastatin 4 and cell death

2012 ◽  
Vol 464 (6) ◽  
pp. 573-582 ◽  
Author(s):  
J. Marc Simard ◽  
S. Kyoon Woo ◽  
Volodymyr Gerzanich
Keyword(s):  
Cell Death ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

scholarly journals Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death

2011 ◽  
Vol 91 (4) ◽  
pp. 677-684 ◽  
Author(s):  
Alvaro Becerra ◽  
Cesar Echeverría ◽  
Diego Varela ◽  
Daniela Sarmiento ◽  
Ricardo Armisén ◽  
...  
Keyword(s):  
Cell Death ◽  
Endothelial Cell ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Endothelial Cell Death ◽  
Transient Receptor
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