Mori Sazanami, Nakamura Natsuki, Fuchigami Ayane, Yoshimoto Satoshi, Sakakibara Moe, Ozawa Toshiyuki, Aoki Junken, Inoue Asuka, Sumida Hayakazu, Ando Hideya, Nakamura Motonao
Department of Bioscience, Graduate School of Life Science Okayama University of Science Okayama Japan.
Department of Dermatology, Faculty of Medicine The University of Tokyo Bunkyo-ku Tokyo Japan.
FASEB Bioadv. 2024 Aug 27;6(10):424-441. doi: 10.1096/fba.2024-00074. eCollection 2024 Oct.
Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non-taste perception and tissue-specific functions. Keratinocytes that express TAS2Rs in the skin provide a first-line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein-coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the G/RhoA/ROCK/p38 MAP kinase/NF-κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling G/RhoA/ROCK/p38 MAP kinase/NF-κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti-toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin.
苦味受体（TAS2Rs）不仅在口腔中表达，也在皮肤中表达。口腔外的TAS2Rs被认为参与非味觉感知和组织特异性功能。在皮肤中表达TAS2Rs的角质形成细胞为抵御外部威胁提供了一线防御。然而，这些受体在宿主防御中的功能作用仍不清楚。在这里，我们证明了细胞内定位的TAS2Rs在角质形成细胞中对有毒物质的感知作用。尽管许多G蛋白偶联受体从细胞表面引发信号，但在人角质形成细胞和HaCaT细胞中发现TAS2Rs定位于细胞内，可能定位于内质网。TAS2R成员之一的TAS2R38在其激动剂苯硫脲（PTC）刺激下激活G/RhoA/ROCK/p38丝裂原活化蛋白激酶/NF-κB途径，导致这些细胞中ABCB1等ABC转运蛋白的产生。值得注意的是，用苦味化合物如PTC和糖精处理可诱导HaCaT细胞中ABCB1的上调。从机制上讲，细胞内的TAS2R38及其下游信号G/RhoA/ROCK/p38丝裂原活化蛋白激酶/NF-κB途径被确定为上述效应的原因。PTC预处理可防止罗丹明123的积累，因为它通过ABCB1排出。此外，PTC或糖精预处理可抵消有毒化合物苯海拉明的作用，并且发现预处理的HaCaT细胞比未处理的细胞增殖更快。维拉帕米（一种ABCB1抑制剂）处理可抑制这种抗毒作用，表明增强的ABCB1有助于清除有毒物质。总之，TAS2Rs的无害激活剂可能是有前景的药物，可增强人体皮肤中有毒物质的排泄。
