AI Article Synopsis
- Major depressive disorder is a serious mental health issue that requires the creation of new, quicker-acting antidepressants.
- Researchers found that inhibiting the Kir4.1 potassium channel in a specific brain area of mice improved symptoms of depression.
- The most effective inhibitor, Lys05, showed rapid antidepressant effects, working as quickly as one hour, and presents Kir4.1 as a viable target for developing fast-acting treatments.
Article Abstract
Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.
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| http://dx.doi.org/10.1038/s41589-024-01555-y | DOI Listing |
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