Kappel, SvenSvenKappelMelek, KorollusKorollusMelek0009-0006-4376-7959Ross-Kaschitza, DanielaDanielaRoss-KaschitzaHauert, BarbaraBarbaraHauertGerber, Christian EliasChristian EliasGerberLochner, MartinMartinLochner0000-0003-4930-1886Peinelt, ChristineChristinePeinelt2024-10-262024-10-262024-03-07https://boris-portal.unibe.ch/handle/20.500.12422/175354Introduction: 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 acidinduced 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 acidinduced 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.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & health500 - Science::540 - Chemistryarticle10.48350/1940423851584810.3389/fphar.2024.1369513