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

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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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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Involvement of transient receptor potential melastatin 4 channels in the resting membrane potential setting and cholinergic contractile responses in mouse detrusor and ileal smooth muscles

Journal of Veterinary Medical Science ◽

10.1292/jvms.18-0631 ◽

2019 ◽

Vol 81 (2) ◽

pp. 217-228 ◽

Cited By ~ 3

Author(s):

Firoj ALOM ◽

Hayato MATSUYAMA ◽

Hiroshi NAGANO ◽

Saki FUJIKAWA ◽

Yasuyuki TANAHASHI ◽

...

Keyword(s):

Membrane Potential ◽

Transient Receptor Potential ◽

Smooth Muscles ◽

Receptor Potential ◽

Resting Membrane Potential ◽

Contractile Responses ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

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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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Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

AJP Cell Physiology ◽

10.1152/ajpcell.00270.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. C600-C611 ◽

Cited By ~ 14

Author(s):

Kiril L. Hristov ◽

Amy C. Smith ◽

Shankar P. Parajuli ◽

John Malysz ◽

Eric S. Rovner ◽

...

Keyword(s):

Smooth Muscle ◽

Transient Receptor Potential ◽

Single Cells ◽

Receptor Potential ◽

Detrusor Smooth Muscle ◽

Rt Pcr ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Trpm4 Channel

Transient receptor potential melastatin 4 (TRPM4) channels are Ca2+-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder.

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TRPM7, Magnesium, and Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20081877 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1877 ◽

Cited By ~ 19

Author(s):

Zhi-Guo Zou ◽

Francisco J. Rios ◽

Augusto C. Montezano ◽

Rhian M. Touyz

Keyword(s):

Growth Factors ◽

Intracellular Signaling ◽

Transient Receptor Potential ◽

Cell Function ◽

Divalent Cations ◽

Receptor Potential ◽

Cellular Functions ◽

Pathological Conditions ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

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 Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

eLife ◽

10.7554/elife.66582 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Guo ◽

Ze-Yan Yu ◽

Jianxin Wu ◽

Hutao Gong ◽

Scott Kesteven ◽

...

Keyword(s):

Ventricular Hypertrophy ◽

Transient Receptor Potential ◽

Pressure Overload ◽

Receptor Potential ◽

Mechanical Stretch ◽

Initial Step ◽

Left Ventricular ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Trpm4 Channel

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

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Cholesterol Stimulates the Transient Receptor Potential Melastatin 4 Channel in mpkCCDc14 Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.627875 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yong-Xu Cai ◽

Bao-Long Zhang ◽

Miao Yu ◽

Yan-Chao Yang ◽

Xue Ao ◽

...

Keyword(s):

Patch Clamp ◽

Transient Receptor Potential ◽

Cholesterol Biosynthesis ◽

Receptor Potential ◽

Water Soluble ◽

Exogenous Cholesterol ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Trpm4 Channel ◽

Inside Out

We have shown that cholesterol regulates the activity of ion channels in mouse cortical collecting duct (CCD) mpkCCDc14 cells and that the transient receptor potential melastatin 4 (TRPM4) channel is expressed in these cells. However, whether TRPM4 channel is regulated by cholesterol remains unclear. Here, we performed inside-out patch-clamp experiments and found that inhibition of cholesterol biosynthesis by lovastatin significantly decreased, whereas enrichment of cholesterol with exogenous cholesterol significantly increased, TRPM4 channel open probability (Po) by regulating its sensitivity to Ca2+ in mpkCCDc14 cells. In addition, inside-out patch-clamp data show that acute depletion of cholesterol in the membrane inner leaflet by methyl-β-cyclodextrin (MβCD) significantly reduced TRPM4 Po, which was reversed by exogenous cholesterol. Moreover, immunofluorescence microscopy, Western blot, cell-surface biotinylation, and patch clamp analysis show that neither inhibition of intracellular cholesterol biosynthesis with lovastatin nor application of exogenous cholesterol had effect on TRPM4 channel protein abundance in the plasma membrane of mpkCCDc14 cells. Sucrose density gradient centrifugation studies demonstrate that TRPM4 was mainly located in cholesterol-rich lipid rafts. Lipid-protein overlay experiments show that TRPM4 directly interacted with several anionic phospholipids, including PI(4,5)P2. Depletion of PI(4,5)P2 with either wortmannin or PGE2 abrogated the stimulatory effects of exogenous cholesterol on TRPM4 activity, whereas exogenous PI(4,5)P2 (diC8-PI(4,5)P2, a water-soluble analog) increased the effects. These results suggest that cholesterol stimulates TRPM4 via a PI(4,5)P2-dependent mechanism.

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TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

International Journal of Molecular Sciences ◽

10.3390/ijms22168502 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8502

Author(s):

Carolina Izquierdo ◽

Mercedes Martín-Martínez ◽

Isabel Gómez-Monterrey ◽

Rosario González-Muñiz

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Structural Knowledge ◽

Structural Studies ◽

Pharmacological Modulation ◽

Cryo Electron Microscopy ◽

Transient Receptor Potential Melastatin ◽

Life Threatening ◽

Transient Receptor ◽

Cold Sensor

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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