Introduction: 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.Methods: 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.Results: In colorectal cancer cells, TMEM206 is not a critical mediator of acid-induced cell death. CBA is a small molecule inhibitor of TMEM206 (IC50 = 9.55 µM) at low pH, at pH 6.0 inhibition is limited.Conclusion: 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.

中文翻译：

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CBA (4-氯-2-(2-氯苯氧基)乙酰氨基) 苯甲酸) 抑制 TMEM206 介导的电流，并且 TMEM206 不会导致结直肠癌细胞中酸诱导的细胞死亡


简介：TMEM206 在低 pH 条件下激活后，可传导 Cl -离子穿过质膜和囊泡膜。据报道，在（病理）生理背景下，TMEM206 会导致神经元、肾脏和宫颈上皮细胞中酸诱导的细胞死亡。我们研究了 TMEM206 在酸诱导的结直肠癌细胞细胞死亡中的作用。此外，我们研究了CBA作为TMEM206的新型小分子抑制剂。方法：通过CRISPR/Cas9介导的基因敲除和FACS分析来研究TMEM206在酸诱导的细胞死亡中的作用。 TMEM206的药理学通过膜片钳技术测定。结果：在结直肠癌细胞中，TMEM206不是酸诱导的细胞死亡的关键介质。 CBA 是 TMEM206 的小分子抑制剂 (IC 50 = 9.55 µM) 在低 pH 条件下，在 pH 6.0 条件下抑制作用有限。结论：CBA 对 TMEM206 具有有效且特异性的抑制作用；然而，其抑制效果在pH 6.0 时有限。尽管存在这一限制，CBA 仍然是 pH 4.5 下功能研究的有效抑制剂，并且可能是未来 TMEM206 抑制剂开发的有前途的支架。