Chronic neuropathic pain is an increasingly prevalent societal issue that responds poorly to existing therapeutic strategies. The α9α10 nicotinic acetylcholine receptor (nAChR) has emerged as a potential target to treat neuropathic pain. However, challenges in expressing functional α9α10 nAChRs in mammalian cell lines have slowed the discovery of α9α10 ligands and studies into the relationship between α9α10 nAChRs and neuropathic pain. Here, we develop a cell line in the HEK293 background that stably expresses functional α9α10 nAChRs. By also developing cell lines expressing only α9 and α10 subunits, we identify distinct receptor pharmacology between homomeric α9 or α10 and heteromeric α9α10 nAChRs. Moreover, we demonstrate that incubation with nAChR ligands differentially regulates the expression of α9- or α10-containing nAChRs, suggesting a possible mechanism by which ligands may modify receptor composition and trafficking in α9- and α10-expressing cells. We then apply our α9α10 cell line in a screen of FDA-approved and investigational drugs to identify α9α10 ligands that provide new tools to probe α9α10 nAChR function. We demonstrate that one compound from this screen, diphenidol, possesses antinociceptive activity in a murine model of neuropathic pain. These results expand our understanding of α9α10 receptor pharmacology and provide new starting points for developing efficacious neuropathic pain treatments.
Discovery of Antinociceptive α9α10 Nicotinic Acetylcholine Receptor Antagonists by Stable Receptor Expression.
阅读:2
作者:Kremiller Kyle M, Kulkarni Gauri C, Harris Lauren M, Gunasekara Hirushi, Kashyap Yavnika, Ilktach Giokdjen, Nguyen Angela, Ondrus Alison E, Hu Ying S, Wang Zaijie J, Riley Andrew P, Peters Christian J
期刊: | ACS Chemical Biology | 影响因子: | 3.800 |
时间: | 2024 | 起止号: | 2024 Nov 15; 19(11):2291-2303 |
doi: | 10.1021/acschembio.4c00330 |
特别声明
1、本文转载旨在传播信息,不代表本网站观点,亦不对其内容的真实性承担责任。
2、其他媒体、网站或个人若从本网站转载使用,必须保留本网站注明的“来源”,并自行承担包括版权在内的相关法律责任。
3、如作者不希望本文被转载,或需洽谈转载稿费等事宜,请及时与本网站联系。
4、此外,如需投稿,也可通过邮箱info@biocloudy.com与我们取得联系。