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FLASH GENE
Symbol TRPM8 contributors: mct/ - updated : 21-06-2016
HGNC name transient receptor potential cation channel, subfamily M, member 8
HGNC id 17961
Location 2q37.1      Physical location : 234.826.042 - 234.928.165
Genatlas name Transient Receptor Potential Melastatin 8
Synonym name
  • cold-menthol receptor type 1
  • short form of the TRPM8 cationic channel
  • long transient receptor potential channel 6
  • Synonym symbol(s) TRPP8, LTRPC6, CMR1, MGC2849
    DNA
    TYPE functioning gene
    STRUCTURE 102.12 kb     26 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    26 - 5621 - 1104 detected in small cell lung carcinoma, choriocarcinoma, and normal liver 2001 11325849
    - - - - - expressed primarily within endoplasmic reticulum membranes of lung epithelial cells 2008 18458237
  • activation of the TRPM8 variant in lung cells was coupled with enhanced expression of the inflammatory cytokines IL6 and IL8
  • may function as a modulator of respiratory physiology caused by cold air, and may partially explain asthmatic respiratory hypersensitivity to cold air
  • - - 722 - 165 expressed in colon tumor, melanoma, prostate, and endometrial adenocarcinoma cell lines 2012 22128173
  • sM8 alpha
  • N-terminal TRPM8 channel fragment
  • generates two distinct proteins, named sM8-6 and sM8-18
  • act as regulatory subunits of the cold/menthol-activated TRPM8 channel
  • mimic heat action rather than chemical inhibitors
  • - - 768 - 192 expressed in colon tumor, melanoma, prostate, and endometrial adenocarcinoma cell lines 2012 22128173
  • sM8 beta
  • N-terminal TRPM8 channel fragment
  • generates only the sM8-6 protein
  • act as regulatory subunits of the cold/menthol-activated TRPM8 channel
  • mimic heat action rather than chemical inhibitors
  • - - - - - localized in the keratinocyte endoplasmic reticulum membrane 2015 26080404
  • controls mitochondrial Ca(2+) concentration
  • controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner
  • EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver     Homo sapiens
    Nervousbrainhindbrainponstrigeminal ganglia 
     gangliasensory gangliadorsal root   Homo sapiens
    Reproductivefemale systembreast    Homo sapiens
     male systemmale genital tract  highly Homo sapiens
     male systemprostate    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Homo sapiens
    cell lineage prostate carcinoma cells
    cell lines
    fluid/secretion sperm
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES Hydrophilic
    STRUCTURE
    motifs/domains
  • a large N terminal hydrophilic domain with eight potential N-linked glycosylation sites, and 30 amino acid signal peptide followed by a 29 AA TIP39 precursor-related peptide
  • seven C terminal transmembrane alpha helices
  • an Arg-Arg processing site, and the actual 39 AA TIP39 sequence
  • a N-x-x-D motif playing specific roles in TRPM8 and TRPM2, reflecting different requirements for voltage-dependent and voltage-independent channel gating
  • region adjacent to the C-end of the inner gate in TRPM8 channels plays a central role in allosteric channel activation
  • C terminus of TRPM8 is known to be regulated by PIP2, which is essential for TRPM8 activity
  • secondary structure transmembrane portion is formed by six helices (termed S1S6)
    mono polymer homomer , tetramer
    HOMOLOGY
    interspecies homolog to rattus Trpm8 (93.7 pc)
    homolog to murine Trpm8 (93.7 pc)
    intraspecies homolog to TRPM2,TRPM1
    Homologene
    FAMILY
  • cold/menthol-sensitive TRP family member
  • LTRPC subfamily
  • TRP superfamily of cation channels
  • CATEGORY protooncogene , receptor , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • expressed in thermosensitive neurons
  • localized in cholesterol-rich specialized membrane domains known as lipid rafts
  • basic FUNCTION
  • receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees celsius
  • involved in menthol sensation
  • cold- and menthol-sensing ion channel that converts thermal and chemical stimuli into neuronal signals and sensations of cooling/cold
  • may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner
  • TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms
  • presence of TRPM8 in sperm, and this channel could be involved in cell signaling events such as thermotaxis or chemotaxis
  • in epidermal keratinocytes plays a role in epidermal permeability barrier homoeostasis and epidermal proliferation after barrier insult
  • might work as cold and l-menthol receptors on tongue
  • major sensor of environmental cold temperatures
  • gated by cold and its chemical agonists directly, and dependence of its gating on PIP4K2A is a result of direct specific interactions with the lipid
  • major cold receptor in the body, but is found in other tissues, including the testis and on the tail and head of spermatozoa
  • acts as a non-painful cooling sensor
  • functions as a cold receptor in sensory neurons
  • could play a modulatory role in cold thermoreceptor activity
  • post-translational modification of TRPM8 is an important mechanism modulating cold thermoreceptor function, explaining the marked differences in temperature sensitivity observed between recombinant and native TRPM8 ion channels
  • N-glycosylation of TRPM8 has an important role in the intrinsic activity of native TRPM8 channels, could play an important modulatory role in sensory neurons, contributing to the setting of the temperature sensitivity of cold thermoreceptor terminals
  • TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain
  • white adipocytes express the cold receptor TRPM8 which activation induces their "browning" supporting a possible role of this receptor in the control of adipose tissue metabolism and body energy balance
  • TRPV1, TRPA1, and TRPM8 are important to start up a systemic response of energy expenditure, energy allocation, and water retention
  • is gated by physiologically relevant cold temperatures and chemical ligands that induce cold sensations, such as the analgesic compound menthol
  • initiated the cold-shock response by differentially modulating cold- and heat-shock proteins
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    text
  • Ca2+ channel
  • PATHWAY
    metabolism
    signaling neurotransmission
    transducer of stimuli in the somatosensory system
    a component homotetramer channel
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • intracellular functional link between CHRM3 and TRPM8 channel via KAT5, suggesting a novel physiological mechanism of arachidonate-mediated regulation of TRPM8 channel activity through muscarinic receptors
  • PIRT regulates the function of TRPM8 and its role in detecting cold
  • activation of OPRM1 leads to internalization of a cold-sensor TRPM8, which can be reversed by a follow-up treatment with the inverse OPRM1 agonist naloxone
  • TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CALCA
  • Ca(2+)-permeable cation channel activated by cold, voltage, phosphatidylinositol 4,5-bisphosphate, and menthol
  • disruption of ZBTB20 in nociceptors led to a marked decrease in the expression levels of TRPV1, TRPA1 and TRPM8
  • TRPM8 channel is physically associated with testosterone, suggesting that, in addition to a genomic role, testosterone plays a role in direct regulation of the TRPM8 channel function
  • TCAF1 and TCAF2 both bind to the TRPM8 channel and promote its trafficking to the cell surface
  • cell & other
    REGULATION
    activated by cold stimuli
    icilin
    eucalyptol
    modulation of intracellular pH
    menthol
    Other regulated by multiple influences such as phosphorylation, pH, Ca(2+), and lipid messengers
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in prostate tumor
    tumoral     --other  
    aberrantly over-expressed in pancreatic adenocarcinoma and required for cellular proliferation
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • clinical biomarker in pancreatic adenocarcinoma
  • Therapy target
    SystemTypeDisorderPubmed
    respiratorylung 
    TRPM8 and TRPA1 agonists may be promising new therapies for asthma
    respiratorylung 
    TRPM8 receptors are possible target for prevention of cold-associated respiratory disorders
    cancerendocrinepancreas
    therapeutic target in pancreatic adenocarcinoma
    ANIMAL & CELL MODELS