Supercooling Agent Icilin Blocks a Warmth-Sensing Ion Channel TRPV3

Transient receptor potential vanilloid subtype 3 (TRPV3) is a thermosensitive ion channel expressed in a variety of neural cells and in keratinocytes. It is activated by warmth (33–39°C), and its responsiveness is dramatically increased at nociceptive temperatures greater than 40°C. Monoterpenoids and 2-APB are chemical activators of TRPV3 channels. We found that Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems like Xenopus laeves oocytes, HEK-293 cells, and in cultured human keratinocytes. Our data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. We hypothesize that blockage of TRPV3 might be a signal for cool-sensing systems (like TRPM8) to beat up the basal activity resulting in increased cold perception when warmth sensors (like TRPV3) are shut off

Menthol Inhibits 5-HT 3

The effects of alcohol monoterpene menthol, a major active in-gredient of the peppermint plant, were tested on the function of human 5-hydroxytryptamine type 3 (5-HT3) receptors expressed in Xenopus laevis oocytes. 5-HT (1 mM)-evoked currents recorded by two-electrode voltage-clamp technique were reversibly inhibited bymenthol in a concentration-dependent (IC505 163mM)manner. The effects of menthol developed gradually, reaching a steady-state level within 10–15 minutes and did not involve G-proteins, since GTPgS activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment. The actions of menthol were not stereoselective as (2), (1), and racemic menthol inhibited 5-HT3 receptor–mediated currents to the same extent. Menthol inhibition was not altered by intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N9,N9-tetraacetic acid injections an

Trigeminal Chemesthesis

In the present chapter we will summarize some important functional properties of the human trigeminal chemosensory system in the nasal, ocular and oral mucosae. Among others, we will address issues related to candidate molecular receptors for trigeminal chemesthesis, chemesthetic sensitivity (i.e., detection thresholds), structure-activity relationships, detection of chemical mixtures, and temporal properties of trigeminal chemesthetic sensations

Pharmacological, biophysical and molecular characterization of thermosensitive recombinant transient receptor potential (TRP) ion channels

Säugetiere nehmen Temperaturen über primäre Neuronen des DRG und trigeminale Ganglionzellen wahr. Diese Zellen detektieren Temperaturen über sogenannte TRP-Ionenkanäle, welche zur Superfamilie der TRP-Kationenkanäle gehören. In der vorliegenden Untersuchung wurden neue Liganden für hTRPA1, TRPV3 und TRPM8 entdeckt. Wir konnten zeigen, dass Mono- und bizyklische Terpenoide die TRPV3 Aktivität unterschiedlich beeinflussen, durch zwei unterschiedliche Bindungsstellen des Rezeptors. Bizyklische Terpenoide wie Kampfer und 1,8-Cineol verursachen eine Desensitisierung von TRPV3. Menthol konnte als aktivierende Substanz für TRPV3 und TRPA1 klassifiziert werden. Interessanterweise konnten wir zeigen, dass Menthol Derivate potenter und spezifischer TRPM8 aktivieren. Nikotin und Analoge von Nikotin stellten sich als Aktivatoren für Schmerzrezeptoren wie hTRPA1 heraus.Mammals sense temperature via primary afferent sensory neurons of the DRG and trigeminal ganglions. The mammalian nervous system performs this function because of the presence of thermo-TRPs, which is a subgroup of TRP-super family of cation channels. In this investigation valuable ligands for hTRPA1, TRPV3 and TRPM8 were discovered. Mono- and bicyclic terpenoids differentially influence TRPV3 activity by binding to different domains. Bicyclic terpenoids like camphor and 1,8-cineol produce robust acute desensitization of TRPV3. Menthol and dihydrocarveol induced tachyphylaxis of TRPV3 responses. Pore-loop mutations resulted in the loss of camphor sensitivity of TRPV3. Menthol was found to activate TRPV3 and TRPA1. Interestingly, menthol-derivatives were found to be more potent and selective for TRPM8. Nicotine and its analogues were found to activate nociceptors like hTRPA1

Borneol inhibits TRPA1, a proinflammatory and noxious pain-sensing cation channel

ABSTRACT: Borneol, a natural product isolated from several species of Artemisia, Blumea and Kaempferia, has a widespread use in traditional medicine. TRP ion channels are a class of nonselective cation channel proteins involved in a variety of physiological and pathological processes in mammals. TRPA1, a member of TRP family of cation channels, is involved in plethora of processes including noxious-cold, noxious-pain sensations, inflammation and the detection of irritant chemicals. Borneol is chemically related to camphor (a known inhibitor of TRPA1 ion channels); therefore, it is beneficial to investigate the effects of borneol on TRPA1. In the present investigation it was found that borneol inhibits TRPA1 mediated cationic currents in low millimolar range (IC 50 0.3mM) in heterologous expression systems like Xenopus oocytes and in neurons cultured from trigeminal ganglia. Effects of nicotine, a known chemical irritant and agonist of TRPA1 are also inhibited by borneol in both systems. It is concluded that borneol, being an inhibitor of TRPA1, could be a safer therapeutic-combination in clinical situations where TRPA1 channelopathies like neuropathicpain, trigeminal neuralgia or nicotine withdrawal treatments are involved