Open AccessKir6.2 activation by sulfonylurea receptors: a different mechanism of action for SUR 1 and SUR 2A subunits via the same residues
Author(s) -
Principalli Maria A.,
Dupuis Julien P.,
Moreau Christophe J.,
Vivaudou Michel,
Revilloud Jean
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12533
Subject(s) - sulfonylurea receptor , kir6.2 , inward rectifier potassium ion channel , potassium channel , transmembrane domain , chemistry , atp binding cassette transporter , microbiology and biotechnology , xenopus , biochemistry , biophysics , protein subunit , ion channel , transporter , biology , receptor , gene
ATP ‐sensitive potassium channels (K‐ ATP channels) play a key role in adjusting the membrane potential to the metabolic state of cells. They result from the unique combination of two proteins: the sulfonylurea receptor ( SUR ), an ATP‐binding cassette ( ABC ) protein, and the inward rectifier K + channel Kir6.2. Both subunits associate to form a heterooctamer (4 SUR /4 Kir6.2). SUR modulates channel gating in response to the binding of nucleotides or drugs and Kir6.2 conducts potassium ions. The activity of K‐ ATP channels varies with their localization. In pancreatic β ‐cells, SUR 1/Kir6.2 channels are partly active at rest while in cardiomyocytes SUR 2A/Kir6.2 channels are mostly closed. This divergence of function could be related to differences in the interaction of SUR 1 and SUR 2A with Kir6.2. Three residues (E1305, I1310, L1313) located in the linker region between transmembrane domain 2 and nucleotide‐binding domain 2 of SUR 2A were previously found to be involved in the activation pathway linking binding of openers onto SUR 2A and channel opening. To determine the role of the equivalent residues in the SUR 1 isoform, we designed chimeras between SUR 1 and the ABC transporter multidrug resistance‐associated protein 1 ( MRP 1), and used patch clamp recordings on Xenopus oocytes to assess the functionality of SUR 1/ MRP 1 chimeric K‐ ATP channels. Our results reveal that the same residues in SUR 1 and SUR 2A are involved in the functional association with Kir6.2, but they display unexpected side‐chain specificities which could account for the contrasted properties of pancreatic and cardiac K‐ ATP channels.