TRPM4 Participates in Aldosterone-Salt-Induced Electrical Atrial Remodeling in Mice

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca2+-transient perturbations and shortening of the action potential. The Ca2+-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The aim of our study was to elucidate the interactions between aldosterone and TRPM4 in atrial remodeling and arrhythmias susceptibility. Hyperaldosteronemia, combined with a high salt diet, was induced in mice by subcutaneously implanted osmotic pumps during 4 weeks, delivering aldosterone or physiological serum for control animals. The experiments were conducted in wild type animals (Trpm4+/+) as well as Trpm4 knock-out animals (Trpm4-/-). The atrial diameter measured by echocardiography was higher in Trpm4-/- compared to Trpm4+/+ animals, and hyperaldosteronemia-salt produced a dilatation in both groups. Action potentials duration and triggered arrhythmias were measured using intracellular microelectrodes on the isolated left atrium. Hyperaldosteronemia-salt prolong action potential in Trpm4-/- mice but had no effect on Trpm4+/+ mice. In the control group (no aldosterone-salt treatment), no triggered arrythmias were recorded in Trpm4+/+ mice, but a high level was detected in Trpm4-/- mice. Hyperaldosteronemia-salt enhanced the occurrence of arrhythmias (early as well as delayed-afterdepolarization) in Trpm4+/+ mice but decreased it in Trpm4-/- animals. Atrial connexin43 immunolabelling indicated their disorganization at the intercalated disks and a redistribution at the lateral side induced by hyperaldosteronemia-salt but also by Trpm4 disruption. In addition, hyperaldosteronemia-salt produced pronounced atrial endothelial thickening in both groups. Altogether, our results indicated that hyperaldosteronemia-salt and TRPM4 participate in atrial electrical and structural remodeling. It appears that TRPM4 is involved in aldosterone-induced atrial action potential shortening. In addition, TRPM4 may promote aldosterone-induced atrial arrhythmias, however, the underlying mechanisms remain to be explored.

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Transient Receptor Potential Melastatin 8 Contributes to Cystitis-Induced Neuronal Sprouting and Pain Hypersensitivity Through AKT/Mtor Signaling Pathway in Interstitial Cystitis/ Bladder Pain Syndrome

10.21203/rs.3.rs-964850/v1 ◽

2021 ◽

Author(s):

Liyang Wu ◽

Fei Zhou ◽

Jianzhong Zhang ◽

Ran Chang ◽

Fei Wang ◽

...

Keyword(s):

Interstitial Cystitis ◽

Transient Receptor Potential ◽

Pain Syndrome ◽

Receptor Potential ◽

Bladder Pain Syndrome ◽

Control Group ◽

Mtor Signaling Pathway ◽

Bladder Pain ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

Abstract Transient receptor potential melastatin 8 (TRPM8) is associated with the pathophysiology of interstitial cystitis (IC)/ bladder pain syndrome (BPS). We investigated the mechanism of TRPM8 in neuroproliferation and pain, as well as the relevance of the Akt/mTOR signaling pathway in mice with IC/BPS. The model of IC/BPS was established in wild and TRPM8-/- mice. The mechanical sensitivity was measured. The number of neurite segments, length of neurites, and density of neurites were all counted. IL-6 and norepinephrine levels were detected by ELISA, Western blot was used to detect protein levels of TRPM8, Akt, p-Akt, mTOR, p-mTOR. Immunofluorescence was used to detect TRPM8 expression and distribution in neurites, neurons, and sensory nerves in mouse bladder tissue. Pain threshold in the IC / BPS group was decreased, and neurite segments, length, and density were all significantly enhanced when compared to the control group. The parameters in the TRPM8 agonists(menthol)+IC/BPS group were more statistically significant. Neurite number and density were lower in TRPM8-/-+IC/BPS mice than in IC/BPS mice. The expression of TRPM8 and the ratios of p-Akt/Akt and p-mTOR/mTOR rose in the IC/BPS group. In TRPM8-/-+IC/BPS mice, the ratios of p-Akt/Akt and p-mTOR/mTOR were not substantially different from those in the control group. TRPM8-/-+IC/BPS mice had considerably lower levels of serum IL-6 and urine norepinephrine than wild-type IC/BPS mice. TRPM8 can induce pain hypersensitivity and sensory nerve proliferation by activating Akt/mTOR pathway and raising the expression of IL-6 and norepinephrine in IC/BPS models. These findings offer new perspectives on IC/BPS treatment.

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Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function

Human Molecular Genetics ◽

10.1093/hmg/ddz198 ◽

2019 ◽

Vol 29 (11) ◽

pp. 1797-1807 ◽

Cited By ~ 1

Author(s):

James H Cartwright ◽

Qadeer Aziz ◽

Stephen C Harmer ◽

Sudhin Thayyil ◽

Andrew Tinker ◽

...

Keyword(s):

Action Potential ◽

Ion Channel ◽

Transient Receptor Potential ◽

Cardiac Development ◽

Receptor Potential ◽

In Utero ◽

Site Directed Mutagenesis ◽

Functional Effect ◽

Channel Function ◽

Transient Receptor Potential Melastatin

Abstract Stillbirth is the loss of a fetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing fetus. We observed four heterozygous, nonsynonymous variants in transient receptor potential melastatin 7 (TRPM7), a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. We used site-directed mutagenesis and single-cell patch-clamp to analyze the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. Our results show that two TRPM7 variants, p.G179V and p.T860M, lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents; however, siRNA knockdown did not directly affect action potential morphology. TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.

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Faculty Opinions recommendation of The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725063502.793517531 ◽

2016 ◽

Author(s):

André Strydom

Keyword(s):

Transient Receptor Potential ◽

Amyloid Β ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Neurovascular Dysfunction

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The TRPM7 Channel in the Nervous and Cardiovascular Systems

Current Protein and Peptide Science ◽

10.2174/1389203721666200605170938 ◽

2020 ◽

Vol 21 (10) ◽

pp. 985-992 ◽

Cited By ~ 1

Author(s):

Koichi Inoue ◽

Zhi-Gang Xiong ◽

Takatoshi Ueki

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Kinase Domain ◽

Cellular Functions ◽

Transient Receptor Potential Melastatin ◽

Cation Permeability ◽

Cardiovascular Systems ◽

Transient Receptor ◽

Excitatory Responses ◽

Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

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Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

Current Neurovascular Research ◽

10.2174/1567202617666200415142211 ◽

2020 ◽

Vol 17 (3) ◽

pp. 249-258 ◽

Cited By ~ 4

Author(s):

Pavan Thapak ◽

Mahendra Bishnoi ◽

Shyam S. Sharma

Keyword(s):

Cognitive Impairment ◽

Cognitive Deficits ◽

Ache Activity ◽

Transient Receptor Potential ◽

Mrna Level ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Trpm2 Channels ◽

Transient Receptor ◽

Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

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Characterization of the function of transient receptor potential melastatin 2 in mouse pancreas

Pancreatology ◽

10.1016/j.pan.2019.05.249 ◽

2019 ◽

Vol 19 ◽

pp. S94

Author(s):

Júlia Fanczal ◽

Petra Pallagi ◽

Marietta Görög ◽

Csaba Péter Bíró ◽

Tamara Madácsy ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Mouse Pancreas ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

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Transient Receptor Potential Melastatin 2 Enhances Vascular Reactivity During Development of Atherosclerosis in Mice

American Journal of Hypertension ◽

10.1093/ajh/hpaa154 ◽

2021 ◽

Vol 34 (1) ◽

pp. 121-122

Author(s):

Yi-quan Dai ◽

Xiao-xiao Yan ◽

Yi-chen Lin ◽

Hong-yu Chen ◽

Xiao-ru Liu

Keyword(s):

Knockout Mice ◽

Vascular Reactivity ◽

Transient Receptor Potential ◽

Gene Knockout ◽

Receptor Potential ◽

Blood Lipid ◽

Normal Diet ◽

Protein Levels ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

Abstract Background To investigate the function of transient receptor potential melastatin 2 (TRPM2) in vascular reactivity induced by 5-hydroxytryptamine (5-HT) in the aorta during development of atherosclerosis in mice. Methods Forty mice were randomly divided into 4 groups: C57BL/6J on normal diet (C57 + ND), C57BL/6J on high-fat diet (C57 + HFD), apolipoprotein E gene knockout mice (ApoE−/−) on ND (ApoE−/− + ND), and ApoE−/− on HFD (ApoE−/− + HFD). They were fed with a ND or HFD for 16 weeks. Aortic TRPM2 expression and isometric contractions were analyzed. Results In the ApoE−/− + HFD group, body weight, blood glucose, and blood lipid concentrations were increased, and aortic plaques were developed. Compared with the other 3 groups, aortic TRPM2 mRNA and protein levels were significantly increased in the ApoE−/− + HFD group (P < 0.01). Aortic reactivity to 5-HT was enhanced in ApoE−/− + HFD mice with lower EC50 values. The enhanced reactivity to 5-HT was significantly inhibited by TRPM2 inhibitors, N-p-amylcinnamoyl anthranilic acid (1 µmol/l) and 2-aminoethyl diphenylborinate (10 µmol/l). Conclusions Aortic TRPM2 expression is upregulated in ApoE knockout mice fed with a HFD. Upregulation of TRPM2 enhances 5-HT vascular reactivity during development of atherosclerosis.

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TRPM4 in Cancer—A New Potential Drug Target

Biomolecules ◽

10.3390/biom11020229 ◽

2021 ◽

Vol 11 (2) ◽

pp. 229

Author(s):

Anna Borgström ◽

Christine Peinelt ◽

Paulina Stokłosa

Keyword(s):

Anticancer Drug ◽

Drug Target ◽

Transient Receptor Potential ◽

Human Cancer ◽

Receptor Potential ◽

B Cell Lymphoma ◽

Underlying Mechanism ◽

Monovalent Cation ◽

Transient Receptor Potential Melastatin ◽

And Migration

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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Reactive Oxygen Species Downregulate Transient Receptor Potential Melastatin 6 Expression Mediated by the Elevation of miR-24-3p in Renal Tubular Epithelial Cells

Cells ◽

10.3390/cells10081893 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1893

Author(s):

Chieko Hirota ◽

Yui Takashina ◽

Yuta Yoshino ◽

Hajime Hasegawa ◽

Ema Okamoto ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Transient Receptor Potential ◽

Reactive Oxygen ◽

Receptor Potential ◽

Fluorescence Measurement ◽

Oxygen Species ◽

Green Fluorescence ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Renal Tubular

Background: A low level of serum magnesium ion (Mg2+) is associated with type 2 diabetes mellitus (T2D). However, the molecular mechanism of Mg2+ deficiency has not been fully clarified. The current study sought to assesses the effect of reactive oxygen species on the expression of Mg2+ channels and miRNA. Methods: The expression of Mg2+ channels and miRNA were examined by real-time polymerase chain reaction. Intracellular Mg2+ concentration was measured by Magnesium Green fluorescence measurement. Results: The mRNA level of transient receptor potential melastatin 6 (TRPM6), which functions as Mg2+ influx channel in the distal convoluted tubule (DCT) of the kidney, was decreased by glycated albumin (GA), but not by insulin in rat renal tubule-derived NRK-52E cells. The mRNA levels of TRPM7, a homologue of TRPM6, and CNNM2, a Mg2+ efflux transporter located at the basolateral membrane of DCT, were changed by neither GA nor insulin. The generation of reactive oxygen species (ROS) was increased by GA. Hydrogen peroxide (H2O2) dose-dependently decreased TRPM6 mRNA, but it inversely increased the reporter activity of TRPM6. H2O2 accelerated the degradation of TRPM6 mRNA in actinomycin D assay without affecting TRPM7 and CNNM2 mRNA expressions. Nine miRNAs were considered as candidates for the regulator of stability of TRPM6 mRNA. Among them, miR-24-3p expression was increased by H2O2. The H2O2-induced reduction of TRPM6 mRNA was rescued by miR-24-3p siRNA. Magnesium Green fluorescence measurement showed that Mg2+ influx is suppressed by H2O2, which was rescued by an antioxidant and miR-24-3p siRNA. Conclusions: We suggest that GA decreases TRPM6 expression mediated by the elevation of ROS and miR-24-3p in renal tubular epithelial cells of T2D.

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Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway

Journal of Vascular Research ◽

10.1159/000512595 ◽

2021 ◽

pp. 1-13

Author(s):

Jiachen Liu ◽

Laijiang Chen ◽

Jun Huang ◽

Shujie Guo ◽

Dingliang Zhu ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

P38 Map Kinase ◽

Inflammatory Factors ◽

Jnk Pathway ◽

Transient Receptor Potential Melastatin ◽

Adventitial Fibroblasts ◽

Phenotypic Transformation ◽

Transient Receptor ◽

Mechanical Stretching

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and speciﬁc anti-TRPM7 small interfering RNA (siRNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.

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