Monoterpenoids Induce Agonist-Specific Desensitization of Transient Receptor Potential Vanilloid-3 (TRPV3) ion Channels

Abstract

Transient receptor potential vanilloid-3 (TRPV3) is a thermo-sensitive ion channel expressed in skin keratinocytes and in a variety of neural cells. It is activated by warmth as well as monoterpenoids including camphor, menthol, dihydrocarveol and 1,8-cineol. TRPV3 is described as a putative nociceptor and previous studies revealed sensitization of the channel during repeated short-term stimulation with different agonists. In the present investigation TRPV3 was transiently expressed in either Xenopus oocytes or HEK293 cells. Whole-cell voltage-clamp techniques were used to characterize the behavior of TRPV3 when challenged with different agonists. Similarly, a human keratinocyte-derived cell line (HaCaT cells) was used to monitor the behavior of native TRPV3 when challenged with different agonists. We report here that prolonged exposure (5-15 minutes) of monoterpenoids results in agonist-specific desensitization of TRPV3. Long-term exposure to camphor and 1,8-cineol elicits desensitizing currents in TRPV3 expressing oocytes, whereas the non-terpenoid agonist 2-APB induces sustained currents. Agonist-specific desensitization of endogenous TRPV3 was also found in HaCaT cells, which may be taken as a representative for the native system. Terpenoids have a long history of use in therapeutics, pharmaceuticals and cosmetics but knowledge about underpinning molecular mechanisms is incomplete. Our finding on agonist-induced desensitization of TRPV3 by some monoterpenoids displays a novel mechanism through which TRP channels could be functionally modulated. Therefore, we conclude that desensitization of TRPV3 channels might be the molecular basis of action for some of the medicinal properties of camphor and 1,8-cineol.

The Ca2+-Permeable Cation Transient Receptor Potential TRPV3 Channel: An Emerging Pivotal Target for Itch and Skin Diseases

“…Some natural plant products, such as camphor, eugenol, carvacrol, thymol, menthol, cinnamaldehyde, and citral, can activate TRPV3 (Xu et al, 2006;Stotz et al, 2008;Sherkheli et al, 2009Sherkheli et al, , 2013Earley et al, 2010;Ortar et al, 2012;Klein et al, 2013). The majority of these natural compounds are commonly known as flavoring ingredients, allergens, and/or skin sensitizers.…”

The monoterpene (–)‐carvone: A novel agonist of TRPV1 channels

“…For instance, camphor activated TRPV1 at 10 mM concentration. Other monoterpenes with similar structure to carvone, have also demonstrated effects on TRPV3 only in the mM range (29,30) and TRPA1 (31).…”

Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship

“…The generation of cRNA was performed by standard methods as described elsewhere (18,34). In brief plasmids, containing cloned cDNA as a template for in vitro transcription, were linearized downstream of the end of the cDNA.…”