Characterization of the mouse cold‐menthol receptor TRPM8 and vanilloid receptor type‐1 VR1 using a fluorometric imaging plate reader (FLIPR) assay

Hj, Behrendt; Germann, Tieno; Gillen, Clemens; Hatt, Hanns; Jostock, Ruth

doi:10.1038/sj.bjp.0705652

Cited by 405 publications

(365 citation statements)

References 45 publications

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“…Published EC 50 values for activation of TRPM8 are, in order of potency, 0.2 Ϯ 0.1 M (icilin) Ͼ 5.9 Ϯ 1.6 mM (geraniol) Ͼ 6.7 Ϯ 2 mM (linalool) Ͼ 7.7 Ϯ 2 mM (eucalyptol) (6). No response was observed upon application of icilin (20 M) or eucalyptol (3 mM) at 33°C (Fig.…”

Section: Pharmacological Properties Ofmentioning

confidence: 93%

TRPM8-independent Menthol-induced Ca2+ Release from Endoplasmic Reticulum and Golgi

Mahieu

Owsianik

Verbert

et al. 2007

Journal of Biological Chemistry

120

105

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Menthol, a secondary alcohol produced by the peppermint herb, Mentha piperita, is widely used in the food and pharmaceutical industries as a cooling/soothing compound and odorant. It induces Ca 2؉ influx in a subset of sensory neurons from dorsal root and trigeminal ganglia, due to activation of TRPM8, a Ca 2؉ -permeable, cold-activated member of the TRP superfamily of cation channels. Menthol also induces Ca 2؉ release from intracellular stores in several TRPM8-expressing cell types, which has led to the suggestion that TRPM8 can function as an intracellular Ca 2؉ -release channel. Here we show that menthol induces Ca 2؉ release from intracellular stores in four widely used cell lines (HEK293, lymph node carcinoma of the prostate (LNCaP), Chinese hamster ovary (CHO), and COS), and provide several lines of evidence indicating that this release pathway is TRPM8-independent: 1) menthol-induced Ca 2؉ release was potentiated at higher temperatures, which contrasts to the cold activation of TRPM8; 2) overexpression of TRPM8 did not enhance the menthol-induced Ca 2؉ release; 3) menthol-induced Ca 2؉ release was mimicked by geraniol and linalool, which are structurally related to menthol, but not by the more potent TRPM8 agonists icilin or eucalyptol; and 4) TRPM8 expression in HEK293 cells was undetectable at the protein and mRNA levels. Moreover, using a novel TRPM8-specific antibody we demonstrate that both heterologously expressed TRPM8 (in HEK293 cells) and endogenous TRPM8 (in LNCaP cells) are mainly localized in the plasma membrane, which contrast to previous localization studies using commercial anti-TRPM8 antibodies. Finally, aequorin-based measurements demonstrate that the TRPM8-independent menthol-induced Ca 2؉ release originates from both endoplasmic reticulum and Golgi compartments.Menthol is a naturally occurring compound responsible for the minty flavor and smell of the mint plant (Mentha piperita). Whereas the first descriptions of the use of menthol as a cooling/soothing compound and odorant date back to ϳ2000 years ago, menthol is still extensively used as an additive in a wide variety of products ranging from ointments and candies to cigarettes. The soothing, refreshing and invigorating feature of the oil made from the peppermint herb is useful in massage for muscle fatigue. It is also used in the treatment of asthma, colic, exhaustion, fever, flatulence, headache, nausea, scabies, sinusitis, and vertigo (1). Currently the best described molecular target of menthol is TRPM8, 2 a member of the melastatin branch of the TRP superfamily of cation channels. TRPM8 was initially identified in a screening procedure aimed at identifying mRNAs that are up-regulated in prostate cancer (2). Subsequently, TRPM8 expression was also demonstrated to be strongly up-regulated in several other primary tumor types including breast, colon, lung, and skin (2). The following studies identified TRPM8 in a subset of dorsal root and trigeminal neurons (3), and found it to function as a plasma membrane Ca 2ϩ -permeable cation ...

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Section: Pharmacological Properties Ofmentioning

confidence: 93%

TRPM8-independent Menthol-induced Ca2+ Release from Endoplasmic Reticulum and Golgi

Mahieu

Owsianik

Verbert

et al. 2007

Journal of Biological Chemistry

120

105

View full text Add to dashboard Cite

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“…Transient receptor potential melastatin 8 (TRPM8), a membrane receptor involved in calcium ion influx and cell signal transduction (Behrendt et al, 2004;Bautista et al, 2007), is over-expressed in melanoma cells and some other types of cancer, such as prostate, breast and colorectal cancers (Zhang and Barritt, 2006;Johnson et al, 2009;Faridi et al, 2011), although in untransformed cells TRPM8 is mainly found in sensory neurons and some epithelial cells, and plays a role in cooling sensation (Bautista et al, 2007;Sabnis et al, 2008;Banner et al, 2011). Although there is a suggestion that TRPM8 is related to tumoriogenesis and cancer cell physiology (Zhang and Barritt, 2006;Prevarskaya et al, 2007a;2007b), there is only limited evidence to support this idea.…”

Section: Dose-dependent Cytotoxic Effects Of Menthol On Human Malignamentioning

confidence: 99%

“…Several reports show that menthol triggers an increase in cytosolic Ca 2+ levels (Behrendt et al, 2004;Yamamura et al, 2008;Kim et al, 2009), leading to downstream Ca 2+ -dependent cell signaling pathways. With respect to its bioactivity, some studies have recently reported on the efficiency of menthol in killing cancer cells such as gastric, leukemia, prostate, colorectal adenocarcinoma and skin (melanoma) cancers (Lin et al, 2005;Lu et al, 2006;Yamamura et al, 2008;Kim et al, 2009;Lu et al, 2009;Faridi et al, 2011), but few studies have pointed out a mechanism.…”

Section: Dose-dependent Cytotoxic Effects Of Menthol On Human Malignamentioning

confidence: 99%

Dose-Dependent Cytotoxic Effects of Menthol on Human Malignant Melanoma A-375 Cells: Correlation with TRPM8 Transcript Expression

Kijpornyongpan

Sereemaspun²,

Chanchao

2014

Asian Pacific Journal of Cancer Prevention

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Background: Transient receptor potential melastatin 8 (TRPM8), a principle membrane receptor involved in calcium ion influx and cell signal transduction, has been found to be up-regulated in some cancer types, including melanomas. Efficiency of menthol, an agonist of TRPM8, in killing melanoma cancer cells has been reported previously, but the mechanisms remain unclear. We here determined whether in vitro cytotoxic effects of menthol on A-375 human malignant melanoma cells might be related to TRPM8 transcript expression. Materials and Methods: The PrestoBlue ® cell viability assay was used to assess the in vitro cytotoxic effect of menthol after 24h of treatment. RT-PCR was used to quantify TRPM8 transcript expression levels in normal and mentholtreated cells. Cell morphology was observed under inverted phase contrast light microscopy. Results: TRPM8 transcript expression was found at low levels in A-375 cells and down-regulated in a potentially dose-dependent manner by menthol. Menthol exerted in vitro cytotoxic effects on A-375 cells with an IC 50 value of 11.8 µM, which was at least as effective as 5-fluorouracil (IC 50 =120 µM), a commonly applied chemotherapeutic drug. Menthol showed no dose-dependent cytotoxicity on HeLa cells, a TRPM8 non-expressing cell line. Conclusions: The cytotoxic effects on A-375 cells caused by menthol might be related to reduction of the TRPM8 transcript level. This suggests that menthol might activate TRPM8 to increase cytosolic Ca 2+ levels, which leads to cytosolic Ca 2+ imbalance and triggers cell death.

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“…In the past, several small molecules (Figure 1) have been reported to show TRPM2 inhibitory activity with variable IC 50 (1.2~76 μ m ), including flufenamic acid (FFA),18, 19 2‐(3‐methylphenyl) aminobenzoic acid (3‐MFA),19 N ‐( p ‐amylcinnamoyl) anthranilic acid (ACA),20 econazole, clotrimazole21 and 2‐aminoethoxydiphenyl borate (2‐APB) 22, 23. However, none of them show any specificity against TRPM2 channel 24.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

Luo

Zhan

et al. 2017

Chem Biol Drug Des

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Transient receptor potential melastatin‐2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′‐diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole‐cell patch‐clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC 50 of 5.7 and 5.4 μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.

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Characterization of the mouse cold‐menthol receptor TRPM8 and vanilloid receptor type‐1 VR1 using a fluorometric imaging plate reader (FLIPR) assay

Cited by 405 publications

References 45 publications

TRPM8-independent Menthol-induced Ca2+ Release from Endoplasmic Reticulum and Golgi

TRPM8-independent Menthol-induced Ca2+ Release from Endoplasmic Reticulum and Golgi

Dose-Dependent Cytotoxic Effects of Menthol on Human Malignant Melanoma A-375 Cells: Correlation with TRPM8 Transcript Expression

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

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