Long-chain acyl-CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of Katp channels by the same mechanism

Schulze, Dirk; Rapedius, Markus; Krauter, Tobias; Baukrowitz, Thomas

doi:10.1111/j.1469-7793.2003.00357.x

Cited by 31 publications

(45 citation statements)

References 32 publications

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“…This is in line with 1) GSIS being unaffected by overexpressed malonyl-CoA decarboxylase (38, but see 39, where overexpression of malonyl-CoA decarboxylase was claimed to suppress GSIS in the presence of added exogenous free fatty acid, but not in their absence), 2) dumping of LCFA-CoA levels by high glucose (40), and 3) Kir6.2 gating by LCFA-CoAs (11,41). It is noteworthy, however, that in light of its glucose specificity, the incretin-like activity of M16 free acid or Cl-DICA (Table 1) may not account for the reported activity of LCFAs in amplifying insulin secretion induced by KCl or arginine (8) or the reported obligatory requirement for LCFAs in KSIS or ArgSIS in fasted rats in vivo (42).…”

Section: Discussionsupporting

confidence: 50%

Modulation of Insulin Secretion by Fatty Acyl Analogs

et al. 2006

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The secretagogue, the incretin-like, and the suppressive activities of long-chain fatty acids (LCFAs) in modulating insulin secretion in vivo and in cultured islets were simulated here by ␤,␤-tetramethyl-hexadecanedioic acid (M16) and ␣,␣-tetrachloro-tetradecanedioic acid (Cl-DICA). M16, but not Cl-DICA, serves as a substrate for ATPdependent CoA thioesterification but is not further metabolized. M16, but not Cl-DICA, acted as a potent insulin secretagogue in islets cultured in basal but not high glucose. Short-term exposure to M16 or Cl-DICA resulted in activation of glucose-but not arginine-stimulated insulin secretion. Long-term exposure to M16, but not to Cl-DICA, resulted in suppression of glucose-, arginine-, and K ؉ -stimulated insulin secretion; inhibition of glucose-induced proinsulin biosynthesis; and depletion of islets insulin. ␤-Cell mass and islet ATP content remained unaffected. Hence, nonmetabolizable LCFA analogs may highlight discrete LCFA metabolites and pathways involved in modulating insulin secretion, which could be overlooked due to the rapid turnover of natural LCFA. Diabetes 55:3478 -3485, 2006

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Section: Discussionsupporting

confidence: 50%

Modulation of Insulin Secretion by Fatty Acyl Analogs

et al. 2006

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“…Of the N-terminal sites, Arg-54 was identified as a major determinant for PIP 2 modulation of ATP sensitivity in the K ATP channels (44) Interestingly, with the possible exception of Arg-201, none of the PIP 2 -sensitive residues overlaps with those of ATP or EET. Recently, long chain acyl-CoA esters were found to modulate ATP inhibition of the K ATP channels by the same mechanisms as PIP 2 (14), suggesting these lipid metabolites shared a common site of interaction on the channel. Indeed, it has been proposed that there is a novel lipid-interacting motif for inward rectifier K ϩ channels termed KIRLI domain (45).…”

Section: Discussionmentioning

confidence: 99%

“…Lipid metabolites are important modulators of the K ATP channels, and these include the long chain acyl-CoA esters (14), phosphatidylinositol 4,5-bisphosphate (PIP 2 ), phosphoinositides (15), L-palmitoylcarnitine (16), and epoxyeicosatrienoic acids (EETs) (17,18). Arachidonic acid is converted by the cytochrome P450 epoxygenase into 4 EET regioisomers, 5.6-, 8,9-, 11,12-, and 14,15-EET ( Fig.…”

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confidence: 99%

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

Lü

Hong

Lee

2005

Journal of Biological Chemistry

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We have previously reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent stereospecific activators of the cardiac K ATP channel. The epoxide group in EET is critical for reducing channel sensitivity to ATP, thereby activating the channel. This study is to identify the molecular sites on the K ATP channels for EET-mediated activation. We investigated the effects of EETs on Kir6.2⌬C26 with or without the coexpression of SUR2A and on Kir6. The cardiac ATP-sensitive K ϩ (K ATP ) 1 channels are biological sensors that respond to intracellular metabolic changes and play important roles in regulating cardiac functions (1). Although the role of the cardiac K ATP channels under normal physiological conditions remains unclear, it is crucial in ischemic preconditioning, and activation of K ATP channels occurs during cardiac ischemia and hypoxia, leading to reduced Ca 2ϩ influx and intracellular Ca 2ϩ overload (2). Some important insights were provided by studies using the Kir6.2 knock-out mice, which have compromised ability in modulating cardiac electrophysiological properties, contractility (3, 4), and in handling cardiac ischemia and stress (3,5,6). Recently, a form of human dilated cardiomyopathy was found to be associated with mutations of the cardiac K ATP channels (7).The cardiac K ATP channel is a heterooctamer containing four inward rectifier K ϩ channel (Kir6.2) and four sulfonylurea receptor (SUR2A) subunits. SUR contains two cytoplasmic nucleotide binding folds that were initially thought to be important for channel regulation by ATP (8). However, a truncation mutant of the Kir6.2 involving deletion of the C-terminal 26 residues (Kir6.2⌬C26) gives rise to channels that retain much of the ATP sensitivity in the absence of SUR (9). Also, mutations in the SUR produced only small effects on ATP inhibition of Kir6.2/SUR currents (10). Previous studies have demonstrated that both the N and C termini of Kir6.2 contribute to the site(s) that regulates ATP sensitivity, and they include Arg-50, Cys-166, Ile-167, Thr-171, Arg-176, Arg-177, Glu-179, Ile-182, Lys-185, Arg-192, Arg-201, and Gly-344 residues. Of these, Arg-50, Lys-185, and Arg-201 residues are particularly crucial for ATP sensitivity and are implicated for interaction with the ␣, ␤, and ␥ phosphates of ATP (11-13). However, the mechanism of Kir6.2 channel inhibition by ATP remains to be elucidated.Lipid metabolites are important modulators of the K ATP channels, and these include the long chain acyl-CoA esters (14), phosphatidylinositol 4,5-bisphosphate (PIP 2 ), phosphoinositides (15), L-palmitoylcarnitine (16), and epoxyeicosatrienoic acids (EETs) (17, 18). Arachidonic acid is converted by the cytochrome P450 epoxygenase into 4 EET regioisomers, 5.6-, 8,9-, 11,12-, and 14,15-EET (Fig. 1) (19). EETs are abundant endogenous constituents of the human and rat hearts, measured at 70 ng of total EETs per g of rat heart (20). 8,9-, 11,12-, and 14,15-EET contribute 39, 28, and 33%, respectively, ...

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“…Opening and closing of the K ATP channel is influenced by the intracellular concentrations of nucleotides (particularly ATP and ADP [8]), lipids such as phosphatidylinositides (9,10), and long-chain acyl-CoA esters (11)(12)(13). Our understanding of how they exert their functional effects has been illuminated by an increasing knowledge of the molecular structure of the K ATP channel.…”

Section: Molecular Biology Of the K Atp Channelmentioning

confidence: 99%

Metabolic Regulation of the Pancreatic Beta-Cell ATP-Sensitive K+ Channel

2004

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Closure of ATP-sensitive K؉ channels (K ATP channels) is a key step in glucose-stimulated insulin secretion. The precise mechanism(s) by which glucose metabolism regulates K ATP channel activity, however, remains controversial. It is widely believed that the principal determinants are the intracellular concentrations of the metabolic ligands, ATP and ADP, which have opposing actions on K ATP channels, with ATP closing and MgADP opening the channel. However, the sensitivity of the channel to these nucleotides in the intact cell, and their relative contribution to the regulation of channel activity, remains unclear. The precise role of phosphoinositides and long-chain acyl-CoA esters, which are capable of modulating the channel ATP sensitivity, is also uncertain. Furthermore, it is still a matter of debate whether it is changes in the concentration of ATP, of MgADP, or of other agents, which couples glucose metabolism to K ATP channel activity. In this article, we review current knowledge of the metabolic regulation of the K ATP channel and provide evidence that MgADP (or MgATP hydrolysis), acting at the regulatory subunit of the channel, shifts the ATP concentration-response curve into a range in which the channel pore can respond to dynamic changes in cytosolic ATP. This metabolic pas de deux orchestrates the pivotal role of ATP in metabolic regulation of the K ATP channel. Diabetes 53 (Suppl. 3): S113-S122, 2004

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Long-chain acyl-CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of Katp channels by the same mechanism

Cited by 31 publications

References 32 publications

Modulation of Insulin Secretion by Fatty Acyl Analogs

Modulation of Insulin Secretion by Fatty Acyl Analogs

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

Metabolic Regulation of the Pancreatic Beta-Cell ATP-Sensitive K+ Channel

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