Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses

Kir4.1 (astrocytic inwardly rectifying potassium channel 4.1) is investigated as a drug target for rapid-onset antidepressant effects. Researchers report discovering a series of Kir4.1 inhibitors via high-throughput screening, highlighting Lys05 as a potent and selective inhibitor. Cryo-electron microscopy plus electrophysiology indicate Lys05 binds directly in the central cavity of Kir4.1. In multiple canonical depression rodent models, a single dose of Lys05 reverses Kir4.1-linked depression-like phenotypes with rapid onset, as early as 1 hour. The reported efficacy is described as comparable to (S)-ketamine, supporting Kir4.1 as a promising target for fast-acting antidepressant strategies.