TUM School of Life Sciences Weihenstephan, Technical University of Munich, Alte Akademie 8, 85354 Freising, Germany.
Leibniz Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354 Freising, Germany.
Int J Mol Sci. 2024 Aug 13;25(16):8829. doi: 10.3390/ijms25168829.
The lysosomal Ca channel TRPML1 was found to be responsible for gastric acid secretion in murine gastric parietal cells by inducing the trafficking of H/K-ATPase containing tubulovesicles to the apical membrane. Therefore, we hypothesized a similar role of TRPML1 in regulating proton secretion in the immortalized human parietal cell line HGT-1. The primary focus was to investigate the involvement of TRPML1 in proton secretion using the known synthetic agonists ML-SA1 and ML-SA5 and the antagonist ML-SI3 and, furthermore, to identify food-derived compounds that target the channel. Proton secretion stimulated by ML-SA1 was reduced by 122.2 ± 22.7% by the antagonist ML-SI3. The steroid hormone 17β-estradiol, present in animal-derived foods, diminished the proton secretory effect of ML-SA1 by 63.4 ± 14.5%. We also demonstrated a reduction in the proton secretory effects of ML-SA1 and ML-SA5 on TRPML1 knock-down cells. The food-derived compounds sulforaphane and trehalose promoted proton secretion in HGT-1 cells but may act independently of TRPML1. Also, histamine- and caffeine-induced proton secretion were affected by neither the TRPML1 antagonist ML-SI3 nor the TRPML1 knock-down. In summary, the results obtained suggest that the activation of TRPML1 promotes proton secretion in HGT-1 cells, but the channel may not participate in canonical signaling pathways.
溶酶体钙通道 TRPML1 被发现通过诱导含有 H/K-ATPase 的小管泡向顶端膜转运，从而负责调节小鼠胃壁细胞的胃酸分泌。因此，我们假设 TRPML1 在调节人永生化胃壁细胞系 HGT-1 中的质子分泌中发挥类似的作用。主要关注的是使用已知的合成激动剂 ML-SA1 和 ML-SA5 以及拮抗剂 ML-SI3 来研究 TRPML1 在质子分泌中的作用，并进一步鉴定靶向该通道的食物来源化合物。通过使用拮抗剂 ML-SI3，ML-SA1 刺激的质子分泌减少了 122.2±22.7%。存在于动物源性食物中的甾体激素 17β-雌二醇也使 ML-SA1 的质子分泌作用减少了 63.4±14.5%。我们还证明了 ML-SA1 和 ML-SA5 对 TRPML1 敲低细胞的质子分泌作用降低。食物来源的化合物萝卜硫素和海藻糖促进了 HGT-1 细胞中的质子分泌，但可能独立于 TRPML1 起作用。此外，组胺和咖啡因诱导的质子分泌既不受 TRPML1 拮抗剂 ML-SI3 的影响，也不受 TRPML1 敲低的影响。总之，研究结果表明，TRPML1 的激活促进了 HGT-1 细胞中的质子分泌，但该通道可能不参与经典的信号通路。
