Structural and functional characterization of the KCNJ6 G154C variant reveals severe GIRK2 channel gain-of-function and opportunities for drug repurposing

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G protein-gated inwardly rectifying potassium (GIRK2) channels regulate neuronal excitability and are implicated in neurodevelopmental disorders. A rare KCNJ6 variant, G154C (hGIRK2 G154C ), was identified in a patient with mild Keppen-Lubinsky syndrome features, contrasting with severe phenotypes linked to other selectivity-filter mutations. Here we combined molecular dynamics simulations and patch-clamp electrophysiology to characterize the hGIRK2 G154C mutant, revealing a widened selectivity filter that resulted in loss of potassium selectivity, aberrant sodium permeation, and loss of inward rectification, indicating a severe gain-of-function phenotype. An in silico and electrophysiological drug screen identified FDA-approved compounds, including nefazodone and eletriptan, that potently inhibited hGIRK2 and hGIRK2 G154C through distinct blocking mechanisms. These findings elucidate the structural and functional impact of the G154C mutation and identify potent pharmacological tools and starting points for therapeutic development in hGIRK2 channelopathies.