8i5n
Rat Kir4.1 in complex with PIP2 and Lys05
Structural highlights
FunctionKCJ10_RAT May be responsible for potassium buffering action of glial cells in the brain. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium. In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules (By similarity).[UniProtKB:P78508] Publication Abstract from PubMedMajor 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. Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.,Zhou X, Zhao C, Xu H, Xu Y, Zhan L, Wang P, He J, Lu T, Gu Y, Yang Y, Xu C, Chen Y, Liu Y, Zeng Y, Tian F, Chen Q, Xie X, Liu J, Hu H, Li J, Zheng Y, Guo J, Gao Z Nat Chem Biol. 2024 Jul;20(7):857-866. doi: 10.1038/s41589-024-01555-y. Epub 2024 , Feb 14. PMID:38355723[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
