TRPM7, Magnesium, and Signaling

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme that possesses an ion channel permeable to the divalent cations Mg2+, Ca2+, and Zn2+, and an α-kinase that phosphorylates downstream substrates. TRPM7 and its homologue TRPM6 have been implicated in a variety of cellular functions and is critically associated with intracellular signaling, including receptor tyrosine kinase (RTK)-mediated pathways. Emerging evidence indicates that growth factors, such as EGF and VEGF, signal through their RTKs, which regulate activity of TRPM6 and TRPM7. TRPM6 is primarily an epithelial-associated channel, while TRPM7 is more ubiquitous. In this review we focus on TRPM7 and its association with growth factors, RTKs, and downstream kinase signaling. We also highlight how interplay between TRPM7, Mg2+ and signaling kinases influences cell function in physiological and pathological conditions, such as cancer and preeclampsia.

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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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The Transient Receptor Potential Melastatin 7 (TRPM7) Inhibitors Suppress Seizure-Induced Neuron Death by Inhibiting Zinc Neurotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms21217897 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7897

Author(s):

Jeong Hyun Jeong ◽

Song Hee Lee ◽

A Ra Kho ◽

Dae Ki Hong ◽

Dong Hyeon Kang ◽

...

Keyword(s):

Transient Receptor Potential ◽

Therapeutic Potential ◽

Divalent Cations ◽

Neurological Diseases ◽

Receptor Potential ◽

Neuron Death ◽

Intracellular Zinc ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Induced Neuron

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood–brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death.

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

10.1101/2021.07.09.451738 ◽

2021 ◽

Author(s):

Astrid Kollewe ◽

Vladimir Chubanov ◽

Fong Tsuen Tseung ◽

Alexander Haupt ◽

Catrin Swantje M&uumlller ◽

...

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 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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Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction

AJP Cell Physiology ◽

10.1152/ajpcell.00349.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. C414-C422 ◽

Cited By ~ 14

Author(s):

Aran Son ◽

Seonghee Park ◽

Dong Min Shin ◽

Shmuel Muallem

Keyword(s):

Intracellular Signaling ◽

Transient Receptor Potential ◽

Cell Function ◽

Receptor Potential ◽

Pancreatic Cell ◽

Pancreatic Acini ◽

Membrane Contact Sites ◽

Recent Advances ◽

Membrane Contact ◽

Transient Receptor

Membrane contact sites (MCS) are critical junctions that form between the endoplasmic reticulum (ER) and membranes of various organelles, including the plasma membrane (PM). Signaling complexes, including mediators of Ca2+signaling, are assembled within MCS, such as the ER/PM junction. This is most evident in polarized epithelial cells, such as pancreatic cells. Core Ca2+signaling proteins cluster at the apical pole, the site of inositol 1,4,5-trisphosphate-mediated Ca2+release and Orai1/transient receptor potential canonical-mediated store-dependent Ca2+entry. Recent advances have characterized the proteins that tether the membranes at MCS and the role of these proteins in modulating physiological and pathological intracellular signaling. This review discusses recent advances in the characterization of Ca2+signaling at ER/PM junctions and the relation of these junctions to physiological and pathological Ca2+signaling in pancreatic acini.

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Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 2: TRPM4 in Health and Disease

Pharmaceuticals ◽

10.3390/ph15010040 ◽

2021 ◽

Vol 15 (1) ◽

pp. 40

Author(s):

Csaba Dienes ◽

Zsigmond Máté Kovács ◽

Tamás Hézső ◽

János Almássy ◽

János Magyar ◽

...

Keyword(s):

Transient Receptor Potential ◽

Divalent Cations ◽

Ischemia Reperfusion ◽

Receptor Potential ◽

Immune Functions ◽

Excitable Cells ◽

Transient Receptor Potential Melastatin ◽

Health And Disease ◽

Transient Receptor ◽

Trpm4 Channel

Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the currently available knowledge about the physiological and pathophysiological roles of TRPM4 in various tissues. These include the physiological functions of TRPM4 in the cells of the Langerhans islets of the pancreas, in various immune functions, in the regulation of vascular tone, in respiratory and other neuronal activities, in chemosensation, and in renal and cardiac physiology. TRPM4 contributes to pathological conditions such as overactive bladder, endothelial dysfunction, various types of malignant diseases and central nervous system conditions including stroke and injuries as well as in cardiac conditions such as arrhythmias, hypertrophy, and ischemia-reperfusion injuries. TRPM4 claims more and more attention and is likely to be the topic of research in the future.

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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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Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4

Pharmaceuticals ◽

10.3390/ph15010081 ◽

2022 ◽

Vol 15 (1) ◽

pp. 81

Author(s):

Zsigmond Máté Kovács ◽

Csaba Dienes ◽

Tamás Hézső ◽

János Almássy ◽

János Magyar ◽

...

Keyword(s):

Membrane Potential ◽

Transient Receptor Potential ◽

Divalent Cations ◽

Receptor Potential ◽

Dominant Negative ◽

Excitable Cells ◽

Pharmacological Modulation ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Trpm4 Channel

Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions by regulating the membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the pharmacological modulation of TRPM4 by listing, comparing, and describing both endogenous and exogenous activators and inhibitors of the ion channel. Moreover, other strategies used to study TRPM4 functions are listed and described. These strategies include siRNA-mediated silencing of TRPM4, dominant-negative TRPM4 variants, and anti-TRPM4 antibodies. TRPM4 is receiving more and more attention and is likely to be the topic of research in the future.

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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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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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