Carvacrol is a novel inhibitor of Drosophila TRPL and mammalian TRPM7 channels

Abstract

Summary TRP channels are essential components of biological sensors that detect changes in the environment in response to a myriad of stimuli. A major difficulty in the study of TRP channels is the lack of pharmacological agents that modulate most members of the TRP superfamily. Notable exceptions are the thermoTRPs, which respond to either cold or hot temperatures and are modulated by a relatively large number of chemical agents. In the present study we demonstrate by patch clamp whole cell recordings from Schneider 2 and Drosophila photoreceptor cells that carvacrol, a known activator of the thermoTRPs, TRPV3 and TRPA1 is an inhibitor of the Drosophila TRPL channels, which belongs to the TRPC subfamily. We also show that additional activators of TRPV3, thymol, eugenol, cinnamaldehyde and menthol are all inhibitors of the TRPL channel. Furthermore, carvacrol also inhibits the mammalian TRPM7 heterologously expressed in HEK cells and ectopically expressed in a primary culture of CA3-CA1 hippocampal brain neurons. This study, thus, identifies a novel inhibitor of TRPC and TRPM channels. Our finding that the activity of the non thermoTRPs, TRPL and TRPM7 channels is modulated by the same compound as thermoTRPs, suggests that common mechanisms of channel modulation characterize TRP channels.

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“…NGF and its receptor, TrkA, reduce this hypoxic overexpression of TRPM7 via a PI3K pathway (Jiang et al, 2008a). In this respect, it is interesting that many exogenous compounds (e.g., ginsenoside and carvacrol) block TRPM7 (Parnas et al, 2009). 5-Lipoxygenase inhibitors are also potent blockers of the channel.…”

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“…Furthermore, the action of carvacrol was also shown to be sufficient to block TRPM7-dependent transmitter release in CA3-CA1 hippocampal neurons overexpressing TRPM7 channels, which is a functional role of TRPM7 that has previously been observed in cholinergic sympathetic neurons [66] . In the same study [65] , drosophila TRPL, which belongs to the TRPC subfamily, was also inhibited by carvacrol. Other than inhibiting TRPM7 and TRPC, carvacrol has shown to activate thermoTRPs, TRPV3, and TRPA1 in earlier study [67] .…”

“…Currently, some non-selective inhibitors are used to assist the understanding of its role in physiological and pathological conditions. These include: trivalent ions, such as Gd 3+ ((IC 50 ~1.4-2.5 μmol/L) and La 3 (IC 50 ~17 μmol/L) [22,62] , 2-aminoethoxydiphenyl borate (2-APB) (IC 50 ~50 μmol/L) [63] , NDGA (nordihydroguaiaretic acid, IC 50 ~6.3 μmol/L) [64] , AA861 (IC 50 ~6.0 μmol/L) [64] , MK886 (IC 50 ~8.6 μmol/L) [64] and carvacrol (IC 50 ~307 μmol/L) [65] . Among these non-selective TRPM7 blockers, a group of 5-lipoxygenase inhibitors (5-LOX), NDGA, AA861, and MK886, showed potent effects on blocking TRPM7 whole-cell current in TRPM7 overexpressing HEK293 cells without affecting the TRPM7 protein expression [64] .…”

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“…For example, Burt et al (2007) show that Escherichia coli treated with carvacrol (1 Mm) produce a signifi cant amount of hsp60. Like thymol, carvacrol is a phenol, which inhibits the function of transient receptor potential-like channels in insects (Parnas et al, 2009).…”