Orth H Noreen, Pirkwieser Philip, Giridhar Maya, Boger Valerie, Somoza Mark M, Dunkel Andreas, Somoza Veronika
Graduate School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
Leibniz-Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany.
Int J Mol Sci. 2025 Sep 19;26(18):9166. doi: 10.3390/ijms26189166.
Beyond sensing bitter-tasting compounds, bitter taste receptors (TAS2Rs) have been demonstrated to play a functional role in proton secretion as a key mechanism of gastric acid secretion (GAS) and the cellular uptake of the zinc metal ion. Given its chemical similarity and comparable effects in GAS, we focused this work on cadmium and hypothesized that gastric TAS2Rs are involved in (i) cadmium-induced inhibition of proton secretion and (ii) in its cellular uptake. To test this hypothesis, immortalized human parietal HGT-1 cells were exposed to 62.5-1000 µM CdCl for 30 min to elucidate TAS2R-mediated proton secretory activity (PSA) using a fluorescence-based pH cell assay and to quantitate cellular cadmium uptake by ICP-MS. HGT-1 cells exposed to CdCl exhibited a dose-dependent decrease in PSA, accompanied by a corresponding increase in intracellular cadmium concentrations. Following a RT-qPCR screening, the functional roles of TAS2R8 and TAS2R10 were clarified using a siRNA knockdown approach, demonstrating that TAS2R8 promotes and TAS2R10 mediates protection against excessive cellular cadmium accumulation. An additional cDNA microarray screening revealed, via gene ontology analysis, a distinct gene association of and with several metal ion transporters. These results provide the first evidence for a specific role of individual TAS2Rs beyond taste perception, particularly in metal ion homeostasis and gastric physiology.
除了感知苦味化合物外，苦味受体（TAS2Rs）已被证明在质子分泌中发挥功能作用，质子分泌是胃酸分泌（GAS）和锌金属离子细胞摄取的关键机制。鉴于镉在胃酸分泌方面的化学相似性和类似作用，我们将这项工作聚焦于镉，并假设胃中的TAS2Rs参与（i）镉诱导的质子分泌抑制和（ii）其细胞摄取过程。为了验证这一假设，将永生化的人胃壁HGT-1细胞暴露于62.5 - 1000 μM的CdCl₂中30分钟，使用基于荧光的pH细胞测定法来阐明TAS2R介导的质子分泌活性（PSA），并通过电感耦合等离子体质谱法（ICP-MS）定量细胞对镉的摄取。暴露于CdCl₂的HGT-1细胞表现出PSA呈剂量依赖性降低，同时细胞内镉浓度相应增加。经过逆转录定量聚合酶链反应（RT-qPCR）筛选后，使用小干扰RNA（siRNA）敲低方法阐明了TAS2R8和TAS2R10的功能作用，表明TAS2R8促进并由TAS2R10介导对细胞内镉过度积累的保护作用。另外的cDNA微阵列筛选通过基因本体分析揭示了TAS2R8和TAS2R10与几种金属离子转运蛋白的独特基因关联。这些结果首次证明了单个TAS2Rs在味觉感知之外的特定作用，特别是在金属离子稳态和胃生理学方面。
