Transient Receptor Potential Ankyrin 1 (TRPA1) channels are multi-modal receptors in animals for sensing noxious physical and chemical factors. They are considered promising biochemical targets for developing repellents of arthropod disease vectors and drugs to treat a variety of medical conditions including pain, inflammation, and itch. Recently, we discovered that cinnamodial (CDIAL), a natural drimane sesquiterpene produced by the medicinal plant Cinnamosma fragrans, activates mosquito TRPA1 channels and is antifeedant and repellent to Aedes aegypti. However, the selectivity of CDIAL for mosquito vs. human TRPA1 and the mechanism(s) of how CDIAL binds to TRPA1 channels are unknown. The first goal of this study was to characterize the activation of Aedes aegypti (Aa) and Homo sapiens (Hs) TRPA1 channels by CDIAL and compare the activation to that of two known TRPA1 agonists, nepetalactone and JT010. Electrophysiological measurements of AaTRPA1 and HsTRPA1 activation (when expressed heterologously in Xenopus laevis oocytes) revealed that CDIAL activated both channels in a similar concentration-dependent manner. Compared to CDIAL, nepetalactone was a less potent agonist of both AaTRPA1 and HsTRPA1, but showed stronger selectivity for AaTRPA1. JT010 did not detectably activate AaTRPA1, but potently activated HsTRPA1. The second goal of this study was to generate insights into a putative binding site of CDIAL on AaTRPA1. We mutated six Lys residues (656, 678, 681, 728, 738, 744) and/or a Cys residue (684) in the coupling domain previously hypothesized to be involved. Simultaneous mutation of the six Lys residues to Ala dampened the electrophysiological activation of AaTRPA1 by CDIAL, whereas changing Cys684 to Ser had no detectable impact. Protein modeling and molecular docking simulations predicted that CDIAL interacts with distinct binding pockets in AaTRPA1 and HsTRPA1 that nonetheless promote similar channel activation, contrasting with JT010, which engages a pocket centered on Cys621 (aligned to Cys684 in AaTRPA1) only in HsTRPA1. These findings illuminate potential species-dependent binding determinants for TRPA1 activation that may lead to the design of novel mosquito-selective repellents and/or TRPA1-targeted therapeutics.

2025-07-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of non-electrophilic TRPA1 channel agonists with anti-nociceptive effects via rapid current desensitization

Article

作者: Wei, Ningning ; Sun, Chaoyue ; Zhang, Yanru ; Wang, KeWei ; Chang, Xiuying ; Zhou, Qiqi ; Yang, Nan ; Qiao, Zhen

Desensitizing transient receptor potential ankyrin 1 (TRPA1) cation channel through agonists emerges as an effective strategy for developing analgesics. Many TRPA1 agonists are electrophilic irritants, including BITC and iodoacetamide (IA), which covalently bind to cysteine residues in the cytoplasmic region of the channel. The electrophile JT010 is also recognized as a potent TRPA1 agonist via covalent modification of Cys621, whose irritant effects have been confirmed in humans, highlighting a commonly undesirable property of these electrophilic agonists. Cryo-electron microscopy (cryo-EM) structures have shown that these electrophiles induce a strong driving force for conformational change through electrophilic modification of TRPA1. However, the stable activated conformation induced by electrophiles might delay subsequent desensitization, leading to prolonged TRPA1-mediated nociception responses in vivo. Therefore, developing non-electrophilic TRPA1 agonists may mitigate the irritation associated with electrophilic agonists by accelerating the desensitizing process. To test this hypothesis, we designed and synthesized a series of novel TRPA1 agonists by removing the electrophilic functional group of JT010. Among these synthetic compounds, whole-cell patch clamp recording assays identified compound 21 as a selective TRPA1 agonist with an EC₅₀ of 25.47 ± 1.56 μM for hTRPA1, exhibiting faster desensitization (τ = 20.02 ± 1.66 s) of mTRPA1 compared to electrophiles JT010 (41.71 ± 4.10 s) and BITC (68.05 ± 5.57 s). Importantly, compound 21 demonstrated effective analgesic properties without irritation in mice. Our findings support the hypothesis that facilitating rapid desensitization of TRPA1 by non-electrophilic channel agonists enhances anti-nociceptive effects. Compound 21 may serve as a promising lead for further optimization.

2023-02-01·Experimental dermatology

TRPA1 promotes UVB‐induced skin pigmentation by regulating melanosome luminal pH

Article

作者: Zhou Li ; Wei Wu ; Zhiqi Song ; Yupeng Wang ; Jing Liu ; Wei Zou ; Handan Guo ; Ying Liu

Abstract:

Melanocytes stimulated by ultraviolet radiation (UVR) produce melanin and melanosomes, which causes skin pigmentation and acts as an important physiological defence process for photoprotection. Neutral luminal pH of melanosomes is critical for providing optimal conditions for the rate‐limiting, pH‐sensitive melanin synthesizing enzyme tyrosinase (TYR). As a major component of extraocular phototransduction pathway, transient receptor potential ankyrin1 (TRPA1) can be activated by ultraviolet B (UVB) and reported to be expressed in melanocytes. However, whether TRPA1 is involved in the regulation of melanogenesis remains unclear. Melanogenic activity of TRPA1 was evaluated in primary normal human epidermal melanocytes (HEMs) and murine B16‐F10 cell cultures, and the effects of topical applications of TRPA1 specific agonist and antagonist on UVB‐induced skin pigmentation were confirmed on in vivo guinea pig models. Calcium (Ca2+) imaging and pH imaging were performed to analyse the effects of TRPA1 on intracellular Ca2+ concentration ([Ca2+]ic) and melanosome luminal pH. TRPA1 regulated melanin synthesis, UVB‐induced Ca2+ influx and melanosome luminal pH in HEMs and B16‐F10 cells. Topical treatment of TRPA1 specific agonist JT010 increased UVB‐induced skin pigmentation in guinea pigs, while topical using of TRPA1 selective antagonist HC‐030031 mitigated such pigmentation. Our results indicated that TRPA1 activated by UVB enhanced the skin pigmentation, most likely by regulating the [Ca2+]ic and the melanosomal pH, consequently influencing the enzymatic activity of TYR. Therefore, the results suggest TRPA1 as a potential therapeutic target in the treatment of skin pigmented disorders that are at high risk under UVB irradiation.

100 项与 JT010 相关的药物交易

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