Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

VAMP7 regulates constitutive membrane incorporation of the cold-activated channel TRPM8.

ABSTRACT: The cation channel TRPM8 plays a central role in the somatosensory system, as a key sensor of innocuously cold temperatures and cooling agents. Although increased functional expression of TRPM8 has been implicated in various forms of pathological cold hypersensitivity, little is known about the cellular and molecular mechanisms that determine TRPM8 abundance at the plasma membrane. Here we demonstrate constitutive transport of TRPM8 towards the plasma membrane in atypical, non-acidic transport vesicles that contain lysosomal-associated membrane protein 1 (LAMP1), and provide evidence that vesicle-associated membrane protein 7 (VAMP7) mediates fusion of these vesicles with the plasma membrane. In line herewith, VAMP7-deficient mice exhibit reduced functional expression of TRPM8 in sensory neurons and concomitant deficits in cold avoidance and icilin-induced cold hypersensitivity. Our results uncover a cellular pathway that controls functional plasma membrane incorporation of a temperature-sensitive TRP channel, and thus regulates thermosensitivity in vivo.

SUBMITTER: Ghosh D

PROVIDER: S-EPMC4742910 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Direct inhibition of the cold-activated TRPM8 ion channel by G?q.

Project description:Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G?(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G?(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G?(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G?(q) protein, but not G??, potently inhibits TRPM8 in excised patches. We conclude that G?(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

| S-EPMC3428855 | biostudies-literature

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

Project description: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 PIP2 in TRPM8. Notably, PIP2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2 and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

| S-EPMC6478609 | biostudies-literature

Constitutive activity of the cation channel TRPM8 regulates the function and differentiation of human monocytes

Project description:This study investigated the impact of TRPM8 activity on human monocyte differentiation and function. CD14+ peripheral blood monocytes were isolated from healthy volunteers and differentiated into macrophages using M-CSF, in the presence or absence of 10μM AMTB (TRPM8 antagonist). RNA seq was performed on CD14+ monocytes and macrophages differentiated in vehicle(Mo-M-DMSO) or AMTB (Mo-M-AMTB). To assess the transcriptional changes that normally occur in monocyte to macrophage differentiaiton we compared the Mo-M-DMSO and CD14+ monocyte samples. 3109 genes were significantly down-regulated and 3403 up-regulated in Mo-M-DMSO samples compared to CD14+ monocytes. To investigate the impact of AMTB upon macrophage differentiation we compared the Mo-M-DMSO and Mo-M-AMTB. 556 genes were significantly lower and 421 genes were significantly higher in Mo-M-AMTB samples compared to Mo-M-DMSO samples. 331 out of the 556 genes lower in Mo-M-AMTB samples were genes that were normally up-regulated during differentiaiton and 253 out of the 421 genes higher in the Mo-M-AMTB samples were genes that were normally down-regulated during differentiation indicating that AMTB predominantly acts to inhibit aspects of the differentiation programme.

2022-05-16 | GSE131415 | GEO

Structure of the cold- and menthol-sensing ion channel TRPM8.

Project description:Transient receptor potential melastatin (TRPM) cation channels are polymodal sensors that are involved in a variety of physiological processes. Within the TRPM family, member 8 (TRPM8) is the primary cold and menthol sensor in humans. We determined the cryo-electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 ångstroms. Our TRPM8 structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation.

| S-EPMC5810135 | biostudies-literature

Rational Design of a Modality-Specific Inhibitor of TRPM8 Channel against Oxaliplatin-Induced Cold Allodynia.

Project description:Platinum-based compounds in chemotherapy such as oxaliplatin often induce peripheral neuropathy and neuropathic pain such as cold allodynia in patients. Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC-1.2 is de novo designed with the optimized hot-spot centric approach. DeC-1.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single-channel patch clamp recordings. It is further demonstrated that DeC-1.2 abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating DeC-1.2 has the potential for further development as a novel analgesic against oxaliplatin-induced neuropathic pain.

| S-EPMC8596132 | biostudies-literature

Drosophila VAMP7 regulates Wingless intracellular trafficking.

Project description:Drosophila Wingless (Wg) is a morphogen that determines cell fate during development. Previous studies have shown that endocytic pathways regulate Wg trafficking and signaling. Here, we showed that loss of vamp7, a gene required for vesicle fusion, dramatically increased Wg levels and decreased Wg signaling. Interestingly, we found that levels of Dally-like (Dlp), a glypican that can interact with Wg to suppress Wg signaling at the dorsoventral boundary of the Drosophila wing, were also increased in vamp7 mutant cells. Moreover, Wg puncta in Rab4-dependent recycling endosomes were Dlp positive. We hypothesize that VAMP7 is required for Wg intracellular trafficking and the accumulation of Wg in Rab4-dependent recycling endosomes might affect Wg signaling.

| S-EPMC5655445 | biostudies-literature

Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation.

Project description:Animals sense cold ambient temperatures through the activation of peripheral thermoreceptors that express TRPM8, a cold- and menthol-activated ion channel. These receptors can discriminate a very wide range of temperatures from innocuous to noxious. The molecular mechanism responsible for the variable sensitivity of individual cold receptors to temperature is unclear. To address this question, we performed a detailed ion channel expression analysis of cold-sensitive neurons, combining bacterial artificial chromosome (BAC) transgenesis with a molecular-profiling approach in fluorescence-activated cell sorting (FACS)-purified TRPM8 neurons. We found that TASK-3 leak potassium channels are highly enriched in a subpopulation of these sensory neurons. The thermal threshold of TRPM8 cold neurons is decreased during TASK-3 blockade and in mice lacking TASK-3, and, most importantly, these mice display hypersensitivity to cold. Our results demonstrate a role of TASK-3 channels in thermosensation, showing that a channel-based combinatorial strategy in TRPM8 cold thermoreceptors leads to molecular specialization and functional diversity.

| S-EPMC5724366 | biostudies-literature

Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner.

Project description:Deviation of the ambient temperature is one of the most ubiquitous stimuli that continuously affect mammals' skin. Although the role of the warmth receptors in epidermal homeostasis (EH) was elucidated in recent years, the mystery of the keratinocyte mild-cold sensor remains unsolved. Here we report the cloning and characterization of a new functional epidermal isoform of the transient receptor potential M8 (TRPM8) mild-cold receptor, dubbed epidermal TRPM8 (eTRPM8), which is localized in the keratinocyte endoplasmic reticulum membrane and controls mitochondrial Ca(2+) concentration ([Ca(2+)]m). In turn, [Ca(2+)]m modulates ATP and superoxide (O2(·-)) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and O2(·-) levels by cooling controls the balance between keratinocyte proliferation and differentiation. Finally, to ascertain eTRPM8's role in EH in vivo we developed a new functional knockout mouse strain by deleting the pore domain of TRPM8 and demonstrated that eTRPM8 knockout impairs adaptation of the epidermis to low temperatures.

| S-EPMC4491737 | biostudies-literature

Constitutive activity of the cation channel TRPM8 regulates the function and differentiation of human monocytes

Project description:Constitutive activity of the cation channel TRPM8 regulates the function and differentiation of human monocytes

| PRJNA543501 | ENA

Coiled coils direct assembly of a cold-activated TRP channel.

Project description:Transient receptor potential (TRP) channels mediate numerous sensory transduction processes and are thought to function as tetramers. TRP channel physiology is well studied; however, comparatively little is understood regarding TRP channel assembly. Here, we identify an autonomously folded assembly domain from the cold- and menthol-gated channel TRPM8. We show that the TRPM8 cytoplasmic C-terminal domain contains a coiled coil that is necessary for channel assembly and sufficient for tetramer formation. Cell biological experiments indicate that coiled-coil formation is required for proper channel maturation and trafficking and that the coiled-coil domain alone can act as a dominant-negative inhibitor of functional channel expression. Our data define an authentic TRP modular assembly domain, establish a clear role for coiled coils in ion channel assembly, demonstrate that coiled-coil assembly domains are a general feature of TRPM channels, and delineate a new tool that should be of general use in dissecting TRPM channel function.

| S-EPMC3014052 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data