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Kir6.2-D323 and SUR2A-Q1336: an intersubunit interaction pairing for allosteric information transfer in the K-ATP channel complex

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journal contribution
posted on 2020-12-02, 10:27 authored by Sean Brennan, Hussein N Rubaiy, Saba Imanzadeh, Ruth Reid, David Lodwick, Robert I Norman, Richard D Rainbow
ATP-sensitive potassium (KATP) channels are widely expressed and play key roles in many tissues by coupling metabolic state to membrane excitability. The SUR subunits confer drug and enhanced nucleotide sensitivity to the pore-forming Kir6 subunit, and so information transfer between the subunits must occur. In our previous study, we identified an electrostatic interaction between Kir6 and SUR2 subunits that was key for allosteric information transfer between the regulatory and pore-forming subunit. In this study, we demonstrate a second putative interaction between Kir6.2-D323 and SUR2A-Q1336 using patch clamp electrophysiological recording, where charge swap mutation of the residues on either side of the potential interaction compromise normal channel function. The Kir6.2-D323K mutation gave rise to a constitutively active, glibenclamide and ATP-insensitive KATP complex, further confirming the importance of information transfer between the Kir6 and SUR2 subunits. Sensitivity to modulators was restored when Kir6.2-D323K was co-expressed with a reciprocal charge swap mutant, SUR-Q1336E. Importantly, equivalent interactions have been identified in both Kir6.1 and Kir6.2 suggesting this is a second important interaction between Kir6 and the proximal C terminus of SUR.

History

Citation

Biochem J (2020) 477 (3): 671–689.

Author affiliation

Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

BIOCHEMICAL JOURNAL

Volume

477

Issue

3

Pagination

671 - 689

Publisher

PORTLAND PRESS LTD

issn

0264-6021

eissn

1470-8728

Acceptance date

2020-01-20

Copyright date

2020

Available date

2020-02-11

Spatial coverage

England

Language

English