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

Theres Friesacher, Haritha P. Reddy, Harald Bernsteiner, J. Carlo Combista, Boris Shalomov, Amal K. Bera, Eva Maria Zangerl-Plessl, Nathan Dascal*, Anna Stary-Weinzinger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

G-protein coupled inwardly rectifying potassium (GIRK) channels are key players in inhibitory neurotransmission in heart and brain. We conducted molecular dynamics simulations to investigate the effect of a selectivity filter (SF) mutation, G154S, on GIRK2 structure and function. We observe mutation-induced loss of selectivity, changes in ion occupancy and altered filter geometry. Unexpectedly, we reveal aberrant SF 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. This study identifies an allosteric connection between the SF and a crucial activator binding site. This allosteric gating mechanism may also apply to other potassium channels that are modulated by accessory proteins.

Original languageEnglish
Article number345
JournalCommunications Biology
Volume5
Issue number1
DOIs
StatePublished - Dec 2022

Funding

FundersFunder number
U.S. Department of Commerce26156
Österreichischen Akademie der WissenschaftenUGC-6-1/2016, ISF_2255_2015
Austrian Science Fund
Israel Science FoundationISF_1282_2018

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