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Transient receptor potential (TRP) channels are a family of non-selective cation channels that are functionally expressed in various organs and cells. Among them, transient receptor potential vanilloid (TRPV) 1 and TRPV4 channels are expressed in T cells, where they serve as Ca 2+ channels for T-cell receptor signaling [Bertin et al., 2014, Majhi et al., 2015]. Here, we show that not only TRPV1 and TRPV4 channel inhibitors, but also a transient receptor potential melastatin (TRPM) 8 channel inhibitor can suppress murine T-cell activation. Mouse splenic lymphocytes pretreated with N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 channel-selective inhibitor, showed significantly reduced IL-2 and IL-6 release from T cells after stimulation with anti-CD3ε/anti-CD28 antibodies or concanavalin A. AMTB also suppressed IL-2 mRNA expression and activation of extracellular signal-regulated kinase 1/2, which is involved in IL-2 production. Further, the increase of CD25 (IL-2 receptor alpha chain) expression after T-cell activation was suppressed by AMTB. TRPM8 channel was expressed in CD4 + T cells isolated from splenocytes, and we confirmed that the release of IL-2 from isolated CD4 + T cells was significantly suppressed by AMTB. In vitro re-stimulation of splenocytes from external antigen-immunized mice with the same antigen induced IL-2 and IL-6 production, which was significantly suppressed by AMTB. Thus, the TRPM8 channel inhibitor AMTB suppresses T-cell activation induced by various stimulants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Transient receptor potential (TRP) channels are known to regulate energy metabolism, and TRPM8 has become an interesting player in this context. Here we demonstrate the role of the cold sensor TRPM8 in the regulation of clock gene and clock controlled genes in brown adipose tissue (BAT). We investigated TrpM8 temporal profile in the eyes, suprachiasmatic nucleus and BAT; only BAT showed temporal variation of TrpM8 transcripts. Eyes from mice lacking TRPM8 lost the temporal profile of Per1 in LD cycle. This alteration in the ocular circadian physiology may explain the delay in the onset of locomotor activity in response to light pulse, as compared to wild type animals (WT). Brown adipocytes from TrpM8 KO mice exhibited a larger multilocularity in comparison to WT or TrpV1 KO mice. In addition, Ucp1 and UCP1 expression was significantly reduced in TrpM8 KO mice in comparison to WT mice. Regarding circadian components, the expression of Per1, Per2, Bmal1, Pparα, and Pparβ oscillated in WT mice kept in LD, whereas in the absence of TRPM8 the expression of clock genes was reduced in amplitude and lack temporal oscillation. Thus, our results reveal new roles for TRPM8 channel: it participates in the regulation of clock and clock-controlled genes in the eyes and BAT, and in BAT thermogenesis. Since disruption of the clock machinery has been associated with many metabolic disorders, the pharmacological modulation of TRPM8 channel may become a promising therapeutic target to counterbalance weight gain, through increased thermogenesis, energy expenditure, and clock gene activation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol's interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca 2+ due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol. In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit's dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)