Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels

Emily B. Pratt, Qing Zhou, Joel W. Gay, Show-Ling Shyng

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The ATP-sensitive potassium (KATP) 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. Crosslinking 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 KATP channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.

Original languageEnglish (US)
Pages (from-to)175-187
Number of pages13
JournalJournal of General Physiology
Volume140
Issue number2
DOIs
StatePublished - Aug 2012

Fingerprint

Sulfonylurea Receptors
KATP Channels
Adenosine Triphosphate
Reducing Agents
Insulin
Mutation
Membranes

ASJC Scopus subject areas

  • Physiology

Cite this

Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels. / Pratt, Emily B.; Zhou, Qing; Gay, Joel W.; Shyng, Show-Ling.

In: Journal of General Physiology, Vol. 140, No. 2, 08.2012, p. 175-187.

Research output: Contribution to journalArticle

@article{f309e86282254dde85078b3daaa89a4a,
title = "Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels",
abstract = "The ATP-sensitive potassium (KATP) 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. Crosslinking 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 KATP channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.",
author = "Pratt, {Emily B.} and Qing Zhou and Gay, {Joel W.} and Show-Ling Shyng",
year = "2012",
month = "8",
doi = "10.1085/jgp.201210803",
language = "English (US)",
volume = "140",
pages = "175--187",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "2",

}

TY - JOUR

T1 - Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels

AU - Pratt, Emily B.

AU - Zhou, Qing

AU - Gay, Joel W.

AU - Shyng, Show-Ling

PY - 2012/8

Y1 - 2012/8

N2 - The ATP-sensitive potassium (KATP) 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. Crosslinking 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 KATP channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.

AB - The ATP-sensitive potassium (KATP) 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. Crosslinking 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 KATP channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.

UR - http://www.scopus.com/inward/record.url?scp=84866172544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866172544&partnerID=8YFLogxK

U2 - 10.1085/jgp.201210803

DO - 10.1085/jgp.201210803

M3 - Article

C2 - 22802363

AN - SCOPUS:84866172544

VL - 140

SP - 175

EP - 187

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 2

ER -