Trigeminal Neuralgia TRPM8 Mutation

Gualdani, Roberta; Yuan, Jun‐Hui; Effraim, Philip R; Stefano, Giulia Di; Truini, Andrea; Cruccu, G.; Dib‐Hajj, Sulayman D.; Gailly, Philippe; Waxman, Stephen G.

doi:10.1212/nxg.0000000000000550

Cited by 16 publications

(10 citation statements)

References 51 publications

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“…Therefore, one possibility is that the TRPM8 phosphorylation pattern could be altered following nerve injury, contributing to the painful phenotype. In this regard, a gain-of-function R30Q mutation in TRPM8 has been recently identified in a patient affected with trigeminal neuralgia (Gualdani et al, 2021). Because of the close proximity of R30 to the S29 residue, we speculate that the R30Q mutation could either prevent the S29 phosphorylation itself or the effect caused by this PTM, explaining the enhanced responses exhibited by this mutation.…”

Section: Discussionmentioning

confidence: 82%

Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function

et al. 2021

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In mammals, environmental cold sensing conducted by peripheral cold thermoreceptor neurons mostly depends on TRPM8, an ion channel that has evolved to become the main molecular cold transducer. This TRP channel is activated by cold, cooling compounds, such as menthol, voltage, and rises in osmolality. TRPM8 function is regulated by kinase activity that phosphorylates the channel under resting conditions. However, which specific residues, how this post-translational modification modulates TRPM8 activity, and its influence on cold sensing are still poorly understood. By mass spectrometry, we identified four serine residues within the N-terminus (S26, S29, S541, and S542) constitutively phosphorylated in the mouse ortholog. TRPM8 function was examined by Ca 21 imaging and patchclamp recordings, revealing that treatment with staurosporine, a kinase inhibitor, augmented its cold-and menthol-evoked responses. S29A mutation is sufficient to increase TRPM8 activity, suggesting that phosphorylation of this residue is a central molecular determinant of this negative regulation. Biophysical and total internal reflection fluorescence-based analysis revealed a dual mechanism in the potentiated responses of unphosphorylated TRPM8: a shift in the voltage activation curve toward more negative potentials and an increase in the number of active channels at the plasma membrane. Importantly, basal kinase activity negatively modulates TRPM8 function at cold thermoreceptors from male and female mice, an observation accounted for by mathematical modeling. Overall, our findings suggest that cold temperature detection could be rapidly and reversibly fine-tuned by controlling the TRPM8 basal phosphorylation state, a mechanism that acts as a dynamic molecular brake of this thermo-TRP channel function in primary sensory neurons.

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Section: Discussionmentioning

confidence: 82%

Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function

et al. 2021

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“…TRPM8 and TRPV4 channels were upregulated in these tissues in contrast to samples from non-symptomatic areas [106]. In cells carrying the Arg30Glu TRPM8 channel mutant, characteristic of familial trigeminal neuralgia, the increased response to menthol (1), was observed through Ca 2+ imaging and Patch-Clamp experiments, indicating that the TRPM8 gain-of-function contributes to pain in this pathology [107]. The predominant involvement of the TRPM8 or TRPA1 channels in cold perception and interspecies dependency is still a matter of controversy.…”

Section: Trpm8 Distribution and Pathological Implicationmentioning

confidence: 90%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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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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“…Considering the role of Ser phosphorylation as a negative TRPM8 modulator, and the importance of conformational flexibility to facilitate phosphorylation, mutant S27P has been suggested to modify the N‐terminal region, preventing its negative modulation. Recently, the R30Q TRPM8 variant has been studied, one of the mutant channels present in patients with trigeminal neuralgia 65 . This is also a gain‐of‐function mutation, with a left‐shift of the voltage curve.…”

Section: Trpm8 Mutantsmentioning

confidence: 99%

“…Recently, the R30Q TRPM8 variant has been studied, one of the mutant channels present in patients with trigeminal neuralgia. 65 This is also a gain-of-function mutation, with a left-shift of the voltage curve.…”

Section: N-terminal Domainmentioning

confidence: 99%

Mutations of TRPM8 channels: Unraveling the molecular basis of activation by cold and ligands

Plaza‐Cayón

González‐Muñiz

Martı́n-Martı́nez

2022

Medicinal Research Reviews

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The cation nonselective channel TRPM8 is activated by multiple stimuli, including moderate cold and various chemical compounds (i.e., menthol and icilin [Fig. 1], among others). While research continues growing on the understanding of the physiological involvement of TRPM8 channels and their role in various pathological states, the information available on its activation mechanisms has also increased, supported by mutagenesis and structural studies. This review compiles known information on specific mutations of channel residues and their consequences on channel viability and function. Besides, the comparison of sequence of animals living in different environments, together with chimera and mutagenesis studies are helping to unravel the mechanism of adaptation to different temperatures. The results of mutagenesis studies, grouped by different channel regions, are compared with the current knowledge of TRPM8 structures obtained by cryo-electron microscopy. Trying to make this review self-explicative and highly informative, important residues for TRPM8 function are summarized in a figure, and mutants, deletions and chimeras are compiled in a table, including also the observed effects by different methods of activation and the corresponding references. The information provided by

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Trigeminal Neuralgia TRPM8 Mutation

Cited by 16 publications

References 51 publications

Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function

Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Mutations of TRPM8 channels: Unraveling the molecular basis of activation by cold and ligands

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