The skin serves as a critical barrier for the body, and maintaining its optimal condition is vital for overall health and well-being. Natural essential oils have been traditionally employed in skin care; however, their specific molecular targets and mechanisms of action have remained largely unknown. This research addresses this gap by exploring how acyclic monoterpenes, the main bioactive components of essential oils, influence skin health. Given the long history of using these natural products for skin maintenance, understanding their molecular basis of action holds significant promise for developing evidence-based skincare strategies.
Methods
The researchers employed a combination of in vivo and in vitro techniques to investigate the effects of acyclic monoterpenes on skin renewal. In vivo studies involved topical application of citronellal, citral, linalool, and isodihydrolavandulal on the skin of wild-type and Trpv3 knockout mice, followed by histological and gene expression analyses. In vitro experiments utilized primary mouse keratinocytes and the human keratinocyte cell line HaCaT to assess cell proliferation and calcium influx upon treatment with these compounds. Electrophysiological recordings, including whole-cell and single-channel patch-clamp techniques, were used to examine the activation of TRPV3 and other TRP channels. Finally, cryo-electron microscopy (cryo-EM) was employed to determine the high-resolution structures of human TRPV3 in complex with these acyclic monoterpenes.
Key Findings
•Citronellal, an acyclic monoterpene, promotes skin renewal by significantly increasing epidermal thickness and keratin stratum thickness in mice. This effect is mediated by enhanced keratinocyte proliferation.
•Citronellal selectively activates the TRPV3 channel in keratinocytes and HEK 293T cells by inducing calcium influx and inward currents. This activation is inhibited by dyclonine, a selective TRPV3 inhibitor.
•TRPV3 deficiency in mice abolishes the skin renewal effects of citronellal and prevents the upregulation of growth factors like TGF-α, TGF-β, VEGF, and TIMP1 in response to citronellal treatment.
•In human keratinocytes (HaCaT cells), citronellal promotes proliferation through TRPV3 activation, leading to Ca2+ influx and subsequent EGFR signaling. This effect is concentration-dependent, with lower concentrations promoting proliferation and higher concentrations showing an inhibitory effect.
•Cryo-EM structures reveal that citronellal, citral, linalool, and isodihydrolavandulal bind to a common hydrophobic vanilloid site within the TRPV3 channel. These ligands exhibit consistent yet subtly different binding modes.
•The binding of these acyclic monoterpenes to TRPV3 involves competitive displacement of endogenous lipids (specifically POPC) from the vanilloid site. Mutations disrupting the interaction between TRPV3 and POPC enhance the potency of these monoterpenes.
•Upon ligand binding and lipid displacement, TRPV3 undergoes conformational changes leading to pore dilation and channel activation. The structures of TRPV3 bound to different ligands represent distinct states within the channel’s gating cycle.
•Similar to citronellal, other acyclic monoterpenes like citral, linalool, and isodihydrolavandulal also activate TRPV3 and promote skin renewal in wild-type mice but not in Trpv3 knockout mice.
This research provides novel insights into the molecular mechanism by which plant-derived acyclic monoterpenes, commonly found in essential oils, exert their beneficial effects on skin renewal. The study unequivocally identifies TRPV3 as a key molecular target for these compounds and elucidates their structural basis of action through competitive displacement of endogenous lipids from the TRPV3 vanilloid binding site. These findings are instrumental for advancing our understanding of TRPV3 pharmacology and its role in skin health. Future implications of this work include the potential for developing targeted TRPV3 modulators based on acyclic monoterpenes for skin healthcare applications, offering a more rational approach to utilizing natural products for skin regeneration and maintenance.
Link to the study: Plant essential oil targets TRPV3 for skin renewal and structural mechanism of action | Nature Communications
