Inhibition of the mitochondrial K(ATP) channel by long-chain acyl-CoA esters and activation by guanine nucleotides

Petr Paucek, Vladimir Yarov-Yarovoy, Xiaocheng Sun, Keith D. Garlid

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

The mitochondrial K(ATP), channel (mitoK(ATP)) is highly sensitive to ATP, which inhibits K+ flux with K( 1/4 ) values of 20-40 μM. This raises the question, how can mitoK(ATP) be opened in the presence of physiological concentrations of ATP? We measured K+ flux in liposomes reconstituted with purified mitoK(ATP) and found that guanine nucleotides are potent activators of this channel. ATP-inhibited K+ flux was completely reactivated by both GTP (K( 1/4 ) = 7 μM) and GDP (K( 1/4 ) = 140 μM). These ligands had no effect in the absence of ATP. The K( 1/4 ) for ATP inhibition exhibited quadratic dependence on [GTP] and [GDP], consistent with two binding sites for guanine nucleotides. We also found that palmitoyl-CoA and oleoyl-CoA inhibited K+ flux through reconstituted mitoK(ATP) with K( 1/4 ) values of 260 nM and 80 nM, respectively. This inhibition was reversed by GTP (K( 1/4 ) = 232 μM) as well as by the K+ channel openers cromakalim (20 μM) and diazoxide (10 μM). Inhibition of mitoK(ATP) by long-chain acyl-CoA esters, like that of ATP, exhibited an absolute requirement for Mg2+ ions. We propose that the open- closed state of the mitochondrial K(ATP) channel is determined by the relative cytosolic concentrations of GTP and long-chain acyl-CoA esters.

Original languageEnglish (US)
Pages (from-to)32084-32088
Number of pages5
JournalJournal of Biological Chemistry
Volume271
Issue number50
DOIs
StatePublished - 1996
Externally publishedYes

Fingerprint

Acyl Coenzyme A
Guanine Nucleotides
Esters
Adenosine Triphosphate
Chemical activation
Guanosine Triphosphate
Fluxes
Cromakalim
Palmitoyl Coenzyme A
Diazoxide
Liposomes
mitochondrial K(ATP) channel
Binding Sites
Ions
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of the mitochondrial K(ATP) channel by long-chain acyl-CoA esters and activation by guanine nucleotides. / Paucek, Petr; Yarov-Yarovoy, Vladimir; Sun, Xiaocheng; Garlid, Keith D.

In: Journal of Biological Chemistry, Vol. 271, No. 50, 1996, p. 32084-32088.

Research output: Contribution to journalArticle

@article{269f75be9c5746e29af79d317c6bf17d,
title = "Inhibition of the mitochondrial K(ATP) channel by long-chain acyl-CoA esters and activation by guanine nucleotides",
abstract = "The mitochondrial K(ATP), channel (mitoK(ATP)) is highly sensitive to ATP, which inhibits K+ flux with K( 1/4 ) values of 20-40 μM. This raises the question, how can mitoK(ATP) be opened in the presence of physiological concentrations of ATP? We measured K+ flux in liposomes reconstituted with purified mitoK(ATP) and found that guanine nucleotides are potent activators of this channel. ATP-inhibited K+ flux was completely reactivated by both GTP (K( 1/4 ) = 7 μM) and GDP (K( 1/4 ) = 140 μM). These ligands had no effect in the absence of ATP. The K( 1/4 ) for ATP inhibition exhibited quadratic dependence on [GTP] and [GDP], consistent with two binding sites for guanine nucleotides. We also found that palmitoyl-CoA and oleoyl-CoA inhibited K+ flux through reconstituted mitoK(ATP) with K( 1/4 ) values of 260 nM and 80 nM, respectively. This inhibition was reversed by GTP (K( 1/4 ) = 232 μM) as well as by the K+ channel openers cromakalim (20 μM) and diazoxide (10 μM). Inhibition of mitoK(ATP) by long-chain acyl-CoA esters, like that of ATP, exhibited an absolute requirement for Mg2+ ions. We propose that the open- closed state of the mitochondrial K(ATP) channel is determined by the relative cytosolic concentrations of GTP and long-chain acyl-CoA esters.",
author = "Petr Paucek and Vladimir Yarov-Yarovoy and Xiaocheng Sun and Garlid, {Keith D.}",
year = "1996",
doi = "10.1074/jbc.271.50.32084",
language = "English (US)",
volume = "271",
pages = "32084--32088",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "50",

}

TY - JOUR

T1 - Inhibition of the mitochondrial K(ATP) channel by long-chain acyl-CoA esters and activation by guanine nucleotides

AU - Paucek, Petr

AU - Yarov-Yarovoy, Vladimir

AU - Sun, Xiaocheng

AU - Garlid, Keith D.

PY - 1996

Y1 - 1996

N2 - The mitochondrial K(ATP), channel (mitoK(ATP)) is highly sensitive to ATP, which inhibits K+ flux with K( 1/4 ) values of 20-40 μM. This raises the question, how can mitoK(ATP) be opened in the presence of physiological concentrations of ATP? We measured K+ flux in liposomes reconstituted with purified mitoK(ATP) and found that guanine nucleotides are potent activators of this channel. ATP-inhibited K+ flux was completely reactivated by both GTP (K( 1/4 ) = 7 μM) and GDP (K( 1/4 ) = 140 μM). These ligands had no effect in the absence of ATP. The K( 1/4 ) for ATP inhibition exhibited quadratic dependence on [GTP] and [GDP], consistent with two binding sites for guanine nucleotides. We also found that palmitoyl-CoA and oleoyl-CoA inhibited K+ flux through reconstituted mitoK(ATP) with K( 1/4 ) values of 260 nM and 80 nM, respectively. This inhibition was reversed by GTP (K( 1/4 ) = 232 μM) as well as by the K+ channel openers cromakalim (20 μM) and diazoxide (10 μM). Inhibition of mitoK(ATP) by long-chain acyl-CoA esters, like that of ATP, exhibited an absolute requirement for Mg2+ ions. We propose that the open- closed state of the mitochondrial K(ATP) channel is determined by the relative cytosolic concentrations of GTP and long-chain acyl-CoA esters.

AB - The mitochondrial K(ATP), channel (mitoK(ATP)) is highly sensitive to ATP, which inhibits K+ flux with K( 1/4 ) values of 20-40 μM. This raises the question, how can mitoK(ATP) be opened in the presence of physiological concentrations of ATP? We measured K+ flux in liposomes reconstituted with purified mitoK(ATP) and found that guanine nucleotides are potent activators of this channel. ATP-inhibited K+ flux was completely reactivated by both GTP (K( 1/4 ) = 7 μM) and GDP (K( 1/4 ) = 140 μM). These ligands had no effect in the absence of ATP. The K( 1/4 ) for ATP inhibition exhibited quadratic dependence on [GTP] and [GDP], consistent with two binding sites for guanine nucleotides. We also found that palmitoyl-CoA and oleoyl-CoA inhibited K+ flux through reconstituted mitoK(ATP) with K( 1/4 ) values of 260 nM and 80 nM, respectively. This inhibition was reversed by GTP (K( 1/4 ) = 232 μM) as well as by the K+ channel openers cromakalim (20 μM) and diazoxide (10 μM). Inhibition of mitoK(ATP) by long-chain acyl-CoA esters, like that of ATP, exhibited an absolute requirement for Mg2+ ions. We propose that the open- closed state of the mitochondrial K(ATP) channel is determined by the relative cytosolic concentrations of GTP and long-chain acyl-CoA esters.

UR - http://www.scopus.com/inward/record.url?scp=0029657912&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029657912&partnerID=8YFLogxK

U2 - 10.1074/jbc.271.50.32084

DO - 10.1074/jbc.271.50.32084

M3 - Article

VL - 271

SP - 32084

EP - 32088

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 50

ER -