A selectivity filter mutation provides insights into gating regulation of a K+ channel.

Abstract

Inwardly rectifying potassium (Kir) channels are essential for numerous physiological processes, including neuronal and cardiac excitability. Recently, the rare Keppen-Lubinsky syndrome (KPLBS), caused by de novo heterozygous mutations in the Kir3.2 (GIRK2) channel, has been described. KPLBS leads to severe developmental and intellectual disabilities, microcephaly, tightly adherent skin, and generalized lipodystrophy. We performed multi-µs molecular dynamics simulations of the WT and mutant GIRK2, which carries a KPLBS-causing point mutation in the selectivity filter. Our simulations provide insights into the structural changes evoked by the KPLBS mutation, as well as the associated molecular mechanisms leading to the loss of K+ selectivity. Furthermore, we reveal aberrant selectivity filter dynamics in the mutant to be correlated with motions in the binding site of the channel activator Gβγ. This coupling is corroborated by electrophysiological experiments, revealing that GIRK2wt activation by Gβγ reduces the affinity of Ba2+ block. We further present a functional characterization of the human GIRK2G154S mutant, validating our computational findings.