Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol

Haeseler, Gertrud; Maue, Danielle K; Großkreutz, Julian; Bufler, J.; Nentwig, B.; Piepenbrock, S.; Dengler, Reinhard; Leuwer, Martin

doi:10.1017/s0265021502000923

Cited by 123 publications

(85 citation statements)

References 45 publications

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“…It is now generally believed that activation of TRPM8 in cold-sensitive neurons of trigeminal and dorsal root ganglia underlies the cooling effect of the menthol (3,4), although characterization of a TRPM8-deficient mouse would be needed to fully prove this point. Moreover, menthol has been shown to inhibit voltage-dependent Na ϩ and Ca 2ϩ channels, which may contribute to the antinociceptive and local anesthetic effects of menthol (21). Interestingly, the sensory impact of menthol on mucosa or skin is clearly biphasic: whereas low doses evoke a cooling sensation, higher concentrations of menthol lead to irritation and even induce a burning feeling (1).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…The interpretation of these studies is further complicated by the findings that menthol is not selective for TRPM8. In fact, menthol was shown to inhibit voltage-gated Na + (Haeseler et al, 2002) and Ca 2+ channels (Swandulla et al, 1987), which could reduce nociceptive transmission. This may explain the observation that responses to menthol were markedly reduced, but not abolished, in TRPM8-null mice (Colburn et al, 2007).…”

Section: Transient Receptor Potential Channels: Acquired Diseasesmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…Menthol is known to cause local anaesthetic effects in neuronal and skeletal muscles via blocking voltage-operated sodium channels (Haeseler et al, 2002). This cellular response has led to its use as a marine anaesthetic (Alexander, 1964;Lauretta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Menthol-induced bleaching rapidly and effectively provides experimental aposymbiotic sea anemones (Aiptasiasp.) for symbiosis investigations

Matthews

Sproles

Oakley

et al. 2015

Journal of Experimental Biology

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Experimental manipulation of the symbiosis between cnidarians and photosynthetic dinoflagellates (Symbiodinium spp.) is crucial to advancing the understanding of the cellular mechanisms involved in host-symbiont interactions, and overall coral reef ecology. The anemone Aiptasia sp. is a model for cnidarian-dinoflagellate symbiosis, and notably it can be rendered aposymbiotic (i.e. dinoflagellate-free) and re-infected with a range of Symbiodinium types. Various methods exist for generating aposymbiotic hosts; however, they can be hugely time consuming and not wholly effective. Here, we optimise a method using menthol for production of aposymbiotic Aiptasia. The menthol treatment produced aposymbiotic hosts within just 4 weeks (97-100% symbiont loss), and the condition was maintained long after treatment when anemones were held under a standard light:dark cycle. The ability of Aiptasia to form a stable symbiosis appeared to be unaffected by menthol exposure, as demonstrated by successful re-establishment of the symbiosis when anemones were experimentally re-infected. Furthermore, there was no significant impact on photosynthetic or respiratory performance of re-infected anemones.

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Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol

Abstract: The results suggest that antinociceptive and local anaesthetic effects of thymol and menthol might be mediated via blockade of voltage-operated sodium channels with the phenol derivative thymol being as potent as the local anaesthetic lidocaine.

Cited by 123 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

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Menthol-induced bleaching rapidly and effectively provides experimental aposymbiotic sea anemones (Aiptasiasp.) for symbiosis investigations

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