TMEM175 has attracted a lot of attention in recent years, both in academia and industry. Its role in lysosomal function and its link to Parkinson\u2019s disease make it an interesting channel to study and a potential therapeutic target. And although we now understand this unusual ion channel much better, we still have a lot to learn about how TMEM175 can be modulated.<\/p>\n
Two recent papers from Jerod Denton and colleagues at Vanderbilt University Medical Center take a closer look at this question.<\/p>\n
The story started with a screen of 960 FDA-approved compounds, which uncovered several new TMEM175 activators. Among them were montelukast and pranlukast, which led the team to test zafirlukast as well. Zafirlukast turned out to be one of the most potent activators in the study.<\/p>\n
From there, the researchers looked more closely at how these compounds act on the channel. Mutagenesis and modeling pointed to residues around T119 and H449 as important for TMEM175 gating and activation.<\/p>\n
Another hit from the same screen was candesartan cilexetil. While candesartan cilexetil activates TMEM175, candesartan itself does not, suggesting that the cilexetil group plays an important role.<\/p>\n
By following this lead and testing new analogs, the team found something particularly interesting: a compound with very little activity on its own could strongly enhance activation by DCPIB.<\/p>\n
Together, these findings expand the pharmacological toolbox for TMEM175 and give us a better view of the different ways this channel can be modulated.<\/p>\n
We are happy to see the SyncroPatch 384PE<\/a> used in this work for direct electrophysiological measurements, helping to validate TMEM175 activation and explore how different compounds act on the channel.<\/p>\n Congratulations to Jerod Denton and all co-authors on these two studies!<\/p>\n <\/p>\n Read the papers here:<\/p>\n https:\/\/journals.physiology.org\/doi\/full\/10.1152\/ajpcell.00951.2025<\/a><\/p>\n