Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels.
The ATP-sensitive potassium (K(ATP)) channel consisting of the inward rectifier Kir6.2 and SUR1 (sulfonylurea receptor 1) couples cell metabolism to membrane excitability and regulates insulin secretion. Inhibition by intracellular ATP is a hallmark feature of the channel. ATP sensitivity is conferred by Kir6.2 but enhanced by SUR1. The mechanism by which SUR1 increases channel ATP sensitivity is not understood. In this study, we report molecular interactions between SUR1 and Kir6.2 that markedly alter channel ATP sensitivity. Channels bearing an E203K mutation in SUR1 and a Q52E in Kir6.2 exhibit ATP sensitivity ∼100-fold higher than wild-type channels. Cross-linking of E203C in SUR1 and Q52C in Kir6.2 locks the channel in a closed state and is reversible by reducing agents, demonstrating close proximity of the two residues. Our results reveal that ATP sensitivity in K(ATP) channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA. pratte@ohsu.edu
Emily B
EB
Pratt
Qing
Q
Zhou
Joel W
JW
Gay
Show-Ling
SL
Shyng
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D015640:Ion Channel Gating; D054086:KATP Channels / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D054086:KATP Channels; D011188:Potassium; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat