Kappel Sven, Melek Korollus, Ross-Kaschitza Daniela, Hauert Barbara, Gerber Christian E, Lochner Martin, Peinelt Christine
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
Front Pharmacol. 2024 Mar 7;15:1369513. doi: 10.3389/fphar.2024.1369513. eCollection 2024.
Upon activation at low pH, TMEM206 conducts Cl ions across plasma and vesicular membranes. In a (patho)physiological context, TMEM206 was reported to contribute to acid-induced cell death in neurons, kidney and cervical epithelial cells. We investigated the role of TMEM206 in acid-induced cell death in colorectal cancer cells. In addition, we studied CBA as a new small molecule inhibitor for TMEM206. The role of TMEM206 in acid-induced cell death was studied with CRISPR/Cas9-mediated knockout and FACS analysis. The pharmacology of TMEM206 was determined with the patch clamp technique. In colorectal cancer cells, TMEM206 is not a critical mediator of acid-induced cell death. CBA is a small molecule inhibitor of TMEM206 (IC = 9.55 µM) at low pH, at pH 6.0 inhibition is limited. CBA demonstrates effective and specific inhibition of TMEM206; however, its inhibitory efficacy is limited at pH 6.0. Despite this limitation, CBA is a potent inhibitor for functional studies at pH 4.5 and may be a promising scaffold for the development of future TMEM206 inhibitors.
在低pH值下被激活后，TMEM206可介导氯离子穿过质膜和囊泡膜。在（病理）生理环境中，据报道TMEM206会导致神经元、肾脏和宫颈上皮细胞发生酸诱导的细胞死亡。我们研究了TMEM206在结肠癌细胞酸诱导的细胞死亡中的作用。此外，我们研究了CBA作为一种针对TMEM206的新型小分子抑制剂。利用CRISPR/Cas9介导的基因敲除和流式细胞术分析研究了TMEM206在酸诱导的细胞死亡中的作用。采用膜片钳技术测定了TMEM206的药理学特性。在结肠癌细胞中，TMEM206不是酸诱导的细胞死亡的关键介质。CBA是一种在低pH值下对TMEM206有抑制作用的小分子抑制剂（IC = 9.55 μM），在pH 6.0时抑制作用有限。CBA对TMEM206具有有效且特异性的抑制作用；然而，其在pH 6.0时的抑制效果有限。尽管存在这一局限性，但CBA在pH 4.5时是用于功能研究的有效抑制剂，并且可能是未来开发TMEM206抑制剂的一个有前景的支架。
