Kir6.2 activation by sulfonylurea receptors: A different mechanism of action for SUR1 and SUR2A subunits via the same residues

Maria A. Principalli, Julien P. Dupuis, Christophe J. Moreau, Michel Vivaudou, Jean Revilloud
Physiol Rep. 2015-09-01; 3(9): e12533
DOI: 10.14814/phy2.12533

PubMed
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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, SUR1/Kir6.2 channels are partly active at
rest while in cardiomyocytes SUR2A/Kir6.2 channels are mostly closed. This
divergence of function could be related to differences in the interaction of SUR1
and SUR2A with Kir6.2. Three residues (E1305, I1310, L1313) located in the linker
region between transmembrane domain 2 and nucleotide-binding domain 2 of SUR2A
were previously found to be involved in the activation pathway linking binding of
openers onto SUR2A and channel opening. To determine the role of the equivalent
residues in the SUR1 isoform, we designed chimeras between SUR1 and the ABC
transporter multidrug resistance-associated protein 1 (MRP1), and used patch
clamp recordings on Xenopus oocytes to assess the functionality of SUR1/MRP1
chimeric K-ATP channels. Our results reveal that the same residues in SUR1 and
SUR2A 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.

© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on
behalf of the American Physiological Society and The Physiological Society.

Auteurs Bordeaux Neurocampus