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

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.

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

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.

scholarly journals Transient Receptor Potential Melastatin 2 Negatively Regulates LPS-ATP-Induced Caspase-1-Dependent Pyroptosis of Bone Marrow-Derived Macrophage by Modulating ROS Production

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Haihong Wang ◽  
Xinyi Zhou ◽  
Hui Li ◽  
Xiaowei Qian ◽  
Yan Wang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Morphological Characteristics ◽  
Receptor Potential ◽  
Ros Production ◽  
Caspase 1 ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Background. Pyroptosis, a new form of cell death, which has special morphological characteristics, depends on caspase-1 activation and occupies an important role in inflammatory immune diseases and ischemia-reperfusion injury. ROS is a common activator of NLR/caspase-1. Transient receptor potential melastatin 2 (TRPM2), a selective cation channel, is involved in inflammatory regulation. This study was designed to explore the role of TRPM2 in activating caspase-1 and caspase-1-dependent pyroptosis of mouse BMDMs. Methods. BMDMs isolated from WT and TRPM2−/− mice were treated with LPS and ATP, along with ROS inhibitor (NAC and DPI), caspase-1 inhibitor (Z-YVAD), or not. The activation of caspase-1 was measured by western blot. EtBr and EthD-2 staining were used to assess the incidence of pyroptosis. Results. Compared with WT, the activated caspase-1-P10 was higher and the percentage of EtBr positive cells was also increased in TRPM2−/− group, which were both inhibited by Z-YVAD, NAC, or DPI. ASC oligomerization was increased in TRPM2−/− group. Conclusion. Deletion of TRPM2 can enhance the activation of caspase-1 and pyroptosis, which may be via modulating ROS production, suggesting that TRPM2 plays a critical role in immune adjustment.

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

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.

Magnesium in Man: Implications for Health and Disease

2015 ◽  
Vol 95 (1) ◽  
pp. 1-46 ◽  
Author(s):  
Jeroen H. F. de Baaij ◽  
Joost G. J. Hoenderop ◽  
René J. M. Bindels
Keyword(s):  
Transient Receptor Potential ◽  
Growth Factor Receptor ◽  
Physiological Role ◽  
Calcineurin Inhibitors ◽  
Receptor Potential ◽  
Enzymatic Reactions ◽  
Comprehensive Overview ◽  
Transient Receptor Potential Melastatin ◽  
Health And Disease ◽  
Transient Receptor

Magnesium (Mg2+) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg2+availability has been proven to be disturbed during several clinical situations, serum Mg2+values are not generally determined in patients. This review aims to provide an overview of the function of Mg2+in human health and disease. In short, Mg2+plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg2+supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg2+transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg2+in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg2+research over the last few decades, focusing on the regulation of Mg2+homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

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

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.

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

2016 ◽  
Vol 310 (7) ◽  
pp. C600-C611 ◽  
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.

scholarly journals TRPM7, Magnesium, and Signaling

2019 ◽  
Vol 20 (8) ◽  
pp. 1877 ◽  
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.

scholarly journals Recent Progress in TRPM8 Modulation: An Update

2019 ◽  
Vol 20 (11) ◽  
pp. 2618 ◽  
Author(s):  
Rosario González-Muñiz ◽  
M. Angeles Bonache ◽  
Cristina Martín-Escura ◽  
Isabel Gómez-Monterrey
Keyword(s):  
Recent Progress ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Short Review ◽  
Pharmacological Characterization ◽  
Trpm8 Channel ◽  
Transient Receptor Potential Melastatin ◽  
Life Threatening ◽  
Health And Disease ◽  
Transient Receptor

The transient receptor potential melastatin subtype 8 (TRPM8) is a nonselective, multimodal ion channel, activated by low temperatures (<28 °C), pressure, and cooling compounds (menthol, icilin). Experimental evidences indicated a role of TRPM8 in cold thermal transduction, different life-threatening tumors, and other pathologies, including migraine, urinary tract dysfunction, dry eye disease, and obesity. Hence, the modulation of the TRPM8 channel could be essential in order to understand its implications in these pathologies and for therapeutic intervention. This short review will cover recent progress on the TRPM8 agonists and antagonists, describing newly reported chemotypes, and their application in the pharmacological characterization of TRPM8 in health and disease. The recently described structures of the TRPM8 channel alone or complexed with known agonists and PIP2 are also discussed.

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

eLife ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document