Alteration of the membrane lipid environment by L -palmitoylcarnitine modulates K ATP channels in guinea-pig ventricular myocytes

Haruna, Tetsuya; Horie, Minoru; Takano, Makoto; Kono, Yutaka; Yoshida, Haruhiko; Otani, Haruhisa; Kubota, Tomoyuki; Ninomiya, T.; Akao, Masaharu; Sasayama, Shígetake

doi:10.1007/s004240000428

Cited by 20 publications

(13 citation statements)

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“…R07H5.2 ( cpt-2 ) is expressed in the adult and larval intestines of C. elegans and has an embryonic lethal RNAi phenotype, whereas Y46G5A.17 ( cpt-1 ) does not have an RNAi phenotype (see below for a detailed explanation) and is expressed in the intestine, body wall muscle, and rectal gland cells in larva and in the pharynx, reproductive system, vulval muscle, and body wall muscle in adults [61]. The chokepoint compound in this reaction, L-palmitoylcarnitine (L-PC) has been shown to inhibit the Na/K pump in guinea-pig ventricular myocytes [62] and the interaction between L-PC and PIP2 in the membrane regulate K ATP channels [63]. A module of the KEGG Fatty Acid Metabolism pathway map is shown in Figure 7A.…”

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confidence: 99%

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

et al. 2013

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Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy.

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Section: Discussionmentioning

confidence: 99%

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

et al. 2013

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“…PC has been shown to cause metabolic, electrical, and mechanical cardiac malfunction (Corr et al, 1979;Sakata et al, 1989;Sato et al, 1992Sato et al, , 1993Tanaka et al, 1992;Wu and Corr, 1992Allely et al, 1993;Shen and Pappano, 1995;Hara et al, 1997;Netticadan et al, 1999;Maruyama et al, 2000). PC alters ion channel function and has been reported to decrease I Ca,L (Wu and Corr, 1992), reduce the open probability of the inward rectifier K ϩ current I K1 (Sato et al, 1993), inhibit I KATP (Haruna et al, 2000), and reduce peak I Na (Sato et al, 1992). PC concentration-and time-dependently increased and then decreased the duration of the action potential of the guinea pig ventricular myocyte (Mészà ros and Pappano, 1990;Shen and Pappano, 1995), induced Ca 2ϩ overload, I Ti , and aftercontractions, and both early and late afterdepolarizations (Meszaros and Pappano, 1990;Wu and Corr, 1992;Shen and Pappano, 1995).…”

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The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction

Wu¹,

Song²,

Belardinelli³

et al. 2009

J Pharmacol Exp Ther

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Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na ϩ and Ca 2ϩ overload and cardiac dysfunction. This study determined whether ranolazine [(Ϯ)-1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]Ϫ] attenuates PC-induced Na ϩ current and ventricular contractile dysfunction of the isolated heart. PC (4 M, 30 min) increased late Na ϩ current by 1034 Ϯ 349% in guinea pig isolated ventricular myocytes; ranolazine (10 M) and tetrodotoxin (TTX, 3 M) significantly attenuated this effect of PC. PC increased left ventricular end-diastolic pressure (LVEDP), coronary perfusion pressure (CPP), wall stiffness, and cardiac lactate and adenosine release from the isolated heart. Ranolazine (10 M) significantly reduced the PC-induced increase in LVEDP by 72 Ϯ 6% (n ϭ 6, p Ͻ 0.001), reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 Ϯ 10% (n ϭ 6 -7, p Ͻ 0.05). Ranolazine (10 M) reduced the PC-induced increases of lactate and adenosine release by 70 Ϯ 8 and 81 Ϯ 5%, respectively (n ϭ 6, p Յ 0.05 for both). TTX (2 M) significantly (p Ͻ 0.05) reduced PC-induced increases of CPP and LVEDP. Pretreatment of isolated myocytes or hearts with the free radical scavenger tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid, disodium salt) (1 mM) significantly reduced the effects of PC to cause increases of late Na ϩ current and LVEDP, respectively, but unlike ranolazine or TTX, tiron did not reverse increases of late Na ϩ current and LVEDP caused by PC. In summary, ranolazine and TTX, inhibitors of the late Na ϩ current, attenuated the PC-induced ventricular contractile dysfunction and increase of coronary resistance in the guinea pig isolated heart. Long-chain acyl carnitines, including palmitoyl-L-carnitine (PC), are intermediates of fatty acid metabolism that accumulate rapidly during brief ischemia (Sobel et al., 1978;DaTorre et al., 1991), secondary to a reduction of tissue oxygenation and mitochondrial lipid oxidation. Hypoxia of 1-h duration was shown to increase the content of long-chain acylcarnitines in sarcolemmal membranes of cultured neonatal rat cardiac myocytes by 70-fold (Knabb et al., 1986). PC has been shown to cause metabolic, electrical, and mechanical cardiac malfunction (Corr et al

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“…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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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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Alteration of the membrane lipid environment by L -palmitoylcarnitine modulates K ATP channels in guinea-pig ventricular myocytes

Cited by 20 publications

References 29 publications

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

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Alteration of the membrane lipid environment by L -palmitoylcarnitine modulates K ATP channels in guinea-pig ventricular myocytes

Cited by 20 publications

References 29 publications

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

The Late Na+ Current (INa) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late INa and Cause Ventricular Diastolic Dysfunction

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

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The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction