Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed membrane protein consisting of ion channel and protein kinase domains. TRPM7 plays a fundamental role in the cellular uptake of divalent cations such as Zn2+, Mg2+ and Ca2+, and thus shapes cellular excitability, plasticity and metabolic activity. The molecular appearance and operation of TRPM7 channel complexes in native tissues have remained unresolved. Here, we investigated the subunit composition of endogenous TRPM7 channels in rodent brain by multi-epitope affinity purification and high-resolution quantitative MS analysis. We found that native TRPM7 channels are high molecular-weight multi-protein complexes that contain the putative metal transporter proteins CNNM1-4 and a small G-protein ARL15. Heterologous reconstitution experiments confirmed the formation of TRPM7/CNNM/ARL15 ternary complexes and indicated that ARL15 effectively and specifically impacts TRPM7 channel activity. These results open up new avenues towards a mechanistic understanding of the cellular regulation and function of TRPM7 channels.

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Transient Receptor Potential Melastatin 4 Channel Controls Calcium Signals and Dental Follicle Stem Cell Differentiation

Stem Cells ◽

10.1002/stem.1264 ◽

2012 ◽

Vol 31 (1) ◽

pp. 167-177 ◽

Cited By ~ 12

Author(s):

Piper Nelson ◽

Tran Doan Ngoc Tran ◽

Hanjie Zhang ◽

Olga Zolochevska ◽

Marxa Figueiredo ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Stem Cell Differentiation ◽

Dental Follicle ◽

Calcium Signals ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

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Deletion of Trpm4 alters the function and expression of NaV1.5 channel in murine cardiac myocytes

10.1101/2020.07.06.188961 ◽

2020 ◽

Author(s):

Ozhathil Lijo Cherian ◽

Jean-Sébastien Rougier ◽

Prakash Arullampalam ◽

Maria C. Essers ◽

Hugues Abriel

Keyword(s):

Cardiac Myocytes ◽

Transient Receptor Potential ◽

Conduction Block ◽

Receptor Potential ◽

Intraventricular Conduction ◽

Cardiac Electrical Activity ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

And Function

AbstractTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca+ -activated non-selective cation channel that is functionally expressed in several tissues including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases including conduction block and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs either in vivo or on Langendorff-perfused explanted mouse hearts. We observed that Trpm4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in the myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+ current observed in the isolated cardiac myocytes. This reduction in Na+ current is explained by the observed decrease in protein expression of NaV1.5 in Trpm4-/- mice. This study suggests that Trpm4 expression impacts Na+ current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.

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The molecular appearance of native TRPM7 channel complexes identified by high-resolution proteomics

eLife ◽

10.7554/elife.68544 ◽

2021 ◽

Vol 10 ◽

Author(s):

Astrid Kollewe ◽

Vladimir Chubanov ◽

Fong Tsuen Tseung ◽

Leonor Correia ◽

Eva Schmidt ◽

...

Keyword(s):

High Resolution ◽

Transient Receptor Potential ◽

Protein Complexes ◽

Divalent Cations ◽

Affinity Purification ◽

Receptor Potential ◽

Metal Transporter ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

And Function

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed membrane protein consisting of ion channel and protein kinase domains. TRPM7 plays a fundamental role in the cellular uptake of divalent cations such as Zn2+, Mg2+ and Ca2+, and thus shapes cellular excitability, plasticity and metabolic activity. The molecular appearance and operation of TRPM7 channel complexes in native tissues have remained unresolved. Here, we investigated the subunit composition of endogenous TRPM7 channels in rodent brain by multi-epitope affinity purification and high-resolution quantitative MS analysis. We found that native TRPM7 channels are high molecular-weight multi-protein complexes that contain the putative metal transporter proteins CNNM1-4 and a small G-protein ARL15. Heterologous reconstitution experiments confirmed the formation of TRPM7/CNNM/ARL15 ternary complexes and indicated that complex formation effectively and specifically impacts TRPM7 activity. These results open up new avenues towards a mechanistic understanding of the cellular regulation and function of TRPM7 channels.

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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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