scholarly journals Implications of Human Transient Receptor Potential Melastatin 8 (TRPM8) Channel Gating from Menthol Binding Studies of the Sensing Domain

Biochemistry ◽  
2015 ◽  
Vol 55 (1) ◽  
pp. 114-124 ◽  
Author(s):  
Parthasarathi Rath ◽  
Jacob K. Hilton ◽  
Nicholas J. Sisco ◽  
Wade D. Van Horn
Keyword(s):  
Transient Receptor Potential ◽  
Channel Gating ◽  
Receptor Potential ◽  
Binding Studies ◽  
Trpm8 Channel ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

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 The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Iordan Iordanov ◽  
Csaba Mihályi ◽  
Balázs Tóth ◽  
László Csanády
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Channel Gating ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chimeric Proteins ◽  
Transient Receptor Potential Melastatin ◽  
Biochemical Studies ◽  
Transient Receptor

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable cation channel essential for immunocyte activation, insulin secretion, and postischemic cell death. TRPM2 is activated by ADP ribose (ADPR) binding to its C-terminal cytosolic NUDT9-homology (NUDT9H) domain, homologous to the soluble mitochondrial ADPR pyrophosphatase (ADPRase) NUDT9. Reported ADPR hydrolysis classified TRPM2 as a channel-enzyme, but insolubility of isolated NUDT9H hampered further investigations. Here we developed a soluble NUDT9H model using chimeric proteins built from complementary polypeptide fragments of NUDT9H and NUDT9. When expressed in E.coli, chimeras containing up to ~90% NUDT9H sequence remained soluble and were affinity-purified. In ADPRase assays the conserved Nudix-box sequence of NUDT9 proved essential for activity (kcat~4-9s-1), that of NUDT9H did not support catalysis. Replacing NUDT9H in full-length TRPM2 with soluble chimeras retained ADPR-dependent channel gating (K1/2~1-5 μM), confirming functionality of chimeric domains. Thus, TRPM2 is not a 'chanzyme'. Chimeras provide convenient soluble NUDT9H models for structural/biochemical studies.

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.

scholarly journals TRPM8 acute desensitization is mediated by calmodulin and requires PIP2: distinction from tachyphylaxis

2011 ◽  
Vol 106 (6) ◽  
pp. 3056-3066 ◽  
Author(s):  
Ignacio Sarria ◽  
Jennifer Ling ◽  
Michael X. Zhu ◽  
Jianguo G. Gu
Keyword(s):  
Transient Receptor Potential ◽  
Channel Gating ◽  
Somatosensory System ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Open Probability ◽  
Cold Environments ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Ganglion Neurons

The cold-sensing channel transient receptor potential melastatin 8 (TRPM8) features Ca2+-dependent downregulation, a cellular process underlying somatosensory accommodation in cold environments. The Ca2+-dependent functional downregulation of TRPM8 is manifested with two distinctive phases, acute desensitization and tachyphylaxis. Here we show in rat dorsal root ganglion neurons that TRPM8 acute desensitization critically depends on phosphatidylinositol 4,5-bisphosphate (PIP2) availability rather than PIP2 hydrolysis and is triggered by calmodulin activation. Tachyphylaxis, on the other hand, is mediated by phospholipase hydrolysis of PIP2 and protein kinase C/phosphatase 1,2A. We further demonstrate that PIP2 switches TRPM8 channel gating to a high-open probability state with short closed times. Ca2+-calmodulin reverses the effect of PIP2, switching channel gating to a low-open probability state with long closed times. Thus, through gating modulation, Ca2+-calmodulin provides a mechanism to rapidly regulate TRPM8 functions in the somatosensory system.

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 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
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