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 Regulation of Activity of Transient Receptor Potential Melastatin 8 (TRPM8) Channel by Its Short Isoforms

2011 ◽  
Vol 287 (5) ◽  
pp. 2948-2962 ◽  
Author(s):  
Gabriel Bidaux ◽  
Benjamin Beck ◽  
Alexander Zholos ◽  
Dmitri Gordienko ◽  
Loic Lemonnier ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpm8 Channel ◽  
Short Isoforms ◽  
Transient Receptor Potential Melastatin ◽  
Regulation Of Activity ◽  
Transient Receptor

scholarly journals Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel

Science ◽  
2019 ◽  
Vol 363 (6430) ◽  
pp. eaav9334 ◽  
Author(s):  
Ying Yin ◽  
Son C. Le ◽  
Allen L. Hsu ◽  
Mario J. Borgnia ◽  
Huanghe Yang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Structural Information ◽  
Receptor Potential ◽  
Membrane Lipid ◽  
Structural Basis ◽  
Trpm8 Channel ◽  
Allosteric Coupling ◽  
Transient Receptor Potential Melastatin ◽  
Lipid Sensing ◽  
Transient Receptor

Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca2+)–permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo–electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP2, and Ca2+, as well as in complex with the menthol analog WS-12 and PIP2. Our structures reveal the binding sites for cooling agonists and PIP2in TRPM8. Notably, PIP2binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

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 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 Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

2016 ◽  
Vol 59 (5) ◽  
pp. 2179-2191 ◽  
Author(s):  
Alessia Bertamino ◽  
Carmine Ostacolo ◽  
Paolo Ambrosino ◽  
Simona Musella ◽  
Veronica Di Sarno ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpm8 Channel ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

scholarly journals TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

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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