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George Lees - One of the best experts on this subject based on the ideXlab platform.
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the sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian cns in vitro
British Journal of Pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P<0.05) than GABA receptors (EC50, 22.12±1.4 μM; Maximum 171%±30, n=11). Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC50 from 322 to 239 μM: P<0.001). Modulation was not voltage-dependent or associated with a shift in Er. β1 containing GABAA receptors (insensitive to many depressant drugs) were positively modulated by Oleamide. Oleamide efficacy was circa 2× greater at α1β1γ2L than α1β2γ2L (P=0.007). Splice variation in γ subunits did not alter Oleamide sensitivity. cis-9,10-Octadecenoamide had no effect on the equilibrium binding of [3H]-muscimol or [3H]-EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid-, benzodiazepine- or barbiturate-like modulator of GABAA-receptors. The transport of [3H]-GABA into mouse brain synaptoneurosomes was unaffected by high micromolar concentrations of cis-9,10-octadecenoamide. Oleamide does not enhance GABA-ergic currents or prolong IPSCs by inhibiting GABA transport. Oleamide is a non-selective modulator of inhibitory ionotropic receptors. The sleep lipid exerts its effects indirectly, or at a novel recognition site on the GABAA complex. Keywords: cis-9,10-octadecenoamide/‘Oleamide' recombinant GABAA receptor, recombinant glycine receptor, human/rat brain receptors and ion channels, [3H]-EBOB and [3H]-muscimol binding, synaptoneurosomes, [3H]-GABA uptake Introduction The fatty acid amide, cis-9,10-octadecenoamide (‘Oleamide' or cOA), was isolated from the cerebrospinal fluid of sleep deprived cats, and synthetic cOA can induce sleep when injected i.p. or i.c.v. into naive animals (Cravatt et al., 1995; Basile et al., 1999). 5HT1, 2 and 7 receptors have been cited as high-affinity targets (Boger et al., 1998a) and 5HT receptors are certainly involved in sleep (Pascoe, 1994) but the concentration of Oleamide required to exert a maximal modulatory response in recombinant 5HT receptors (Huidobro Toro & Harris, 1996) is below the physiological range of Oleamide reported in the CSF of even alert animals (Basile et al., 1999). In contrast, at concentrations greater than 10 μM, Oleamide can uncouple gap junctions (Boger et al., 1998b). It has been suggested that cOA blocks gap junctions by increasing the membrane homeoviscosity of neurones (Lerner, 1997). Others suggest that although Oleamide (>10 μM) can fluidize membranes this is not relevant to sleep induction, but their ex vivo experiments suggest that sleep-inducing doses of the lipid result in very high brain concentrations (Gobbi et al., 1999). Oleamide is broken down by fatty acid amide hydrolase (FAAH) enzymes, which also degrade the endocannabinoid anandamide. Exogenous Oleamide's effects on locomotor activity (Cheer et al., 1999) and sleep are broadly cannabinomimetic (Mendelson & Basile, 1999). However, Oleamide binds only weakly to CB1 receptors (Cheer et al., 1999) and it cannot directly alter GTPγS binding (Boring et al., 1996). A popular interpretation of the above evidence is that Oleamide competes with anandamide for FAAH, causing the levels of anandamide to increase thus producing sleep (Cheer et al., 1999). We have highlighted that GABAA receptors (see also Yost et al., 1998) and voltage-gated sodium channels are both stereoselectively modulated by Oleamide (trans-Oleamide was much less potent as a sleep inducer and is not active at these presumptive targets in vitro) (Laws et al., 2001). Sodium channels are blocked by Oleamide in a state/voltage-dependent manner, which is an acknowledged effect of several classes of depressant drug (Verdon et al., 2000; Nicholson et al., 2001). GABAA receptor currents are enhanced in the presence of Oleamide (Lees et al., 1998). The modulatory effects of Oleamide on GABAA receptors, and the fact that it blocks voltage-gated sodium channels in a manner similar to anaesthetic and anticonvulsant drugs, suggests that this or related lipids may be endogenous ligands for drug recognition sites (Laws et al., 2001). Most anaesthetics (with the exception of ketamine, nitrous oxide and xenon) are demonstrably active at GABAA receptors, where their potency mirrors their anaesthetic potency in vivo (Franks & Lieb, 1994; Laws et al., 2001). Glycine receptors share sensitivity to a variety of anaesthetics and were an important tool in seeking key anaesthetic recognition domains on the GABAA receptor protein (Belelli et al., 1999b). The β subunit of the GABAA receptor and the α subunit of the glycine receptor contain sites on the M2 and M3 domains which are crucial for modulatory effects of depressant drugs. These sites confer sensitivity of the receptor not only to anaesthetics but also to the anticonvulsant loreclazole (Wafford et al., 1994) and the recently disclosed depressant effects of NSAIDS (Halliwell et al., 1999). Naturally occurring subunit combinations (isoforms) of the GABAA receptor show differing sensitivity to volatile anaesthetics, with the β1 containing receptors being insensitive. The β1 and β2 subunits contain different amino acid residues (β1, Ser-290, β2, Asn-289) in the M2 domain leading to the insensitivity of β1 to etomidate and loreclazole (Belelli et al., 1997). The M2 domain on both the α and β subunits confers absolute sensitivity to two volatile anaesthetics and ethanol (Mihic et al., 1997). A later publication by Krasowski & Harrison (2000) showed that 12 out of 13 general anaesthetics, including isoflurane and enflurane, had a reduced or no modulatory effect on GABA receptors containing mutations in the M2 domain of α and/or β subunits. This site on the M2 domain may represent a site for direct binding of Oleamide to the GABAA receptor although the GABAA receptor-chloride ion channel has a remarkable capacity for allosteric regulation by both drugs and steroid hormones. In this study we examine the sensitivity of glycine receptor subunits to modulation by Oleamide. Furthermore, we probe the influence of GABAA β subunits and of splice variation in γ subunits (which alter the sensitivity to ethanol) on Oleamide modulation. Biochemical experiments on GABA uptake and EBOB/muscimol binding are used to seek a mechanism for potentiation of chloride currents by Oleamide.
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The sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro
British journal of pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P
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Stereoselective modulatory actions of Oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS
British journal of pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, C Robin Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
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stereoselective modulatory actions of Oleamide on gabaa receptors and voltage gated na channels in vitro a putative endogenous ligand for depressant drug sites in cns
British Journal of Pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, Robin C Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
Benjamin F Cravatt - One of the best experts on this subject based on the ideXlab platform.
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2016Co-Authors: Transmission In Glial Cells, Dale L Boger, Benjamin F Cravatt, Xiaojun Guan, George R. Ehring, James E. Hall, Richard A. LernerAbstract:Oleamide is a sleep-inducing lipid originally isolated from the cerebrospinal fluid of sleep-deprived cats. Oleamide was found to potently and selectively in-activate gap junction–mediated communication be-tween rat glial cells. In contrast, Oleamide had no effect on mechanically stimulated calcium wave transmission in this same cell type. Other chemical compounds tradi-tionally used as inhibitors of gap junctional communi-cation, like heptano
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The Endogenous Lipid Oleamide Activates Serotonin 5-HT7 Neurons in Mouse Thalamus and Hypothalamus
2015Co-Authors: Elizabeth A. Thomas, Benjamin F Cravatt, Gregor J. SutcliffeAbstract:Abstract: Oleamide is an endogenous lipid that accumu-lates during sleep deprivation and has hypothermic ef-fects when administered to rodents. The mechanisms for its activity remain unknown. Intraperitoneal injections of Oleamide elicited dramatic increases in content of c-fos mRNA and Fos protein in distinct brain regions, including cingulate and somatosensory cortical areas and numer-ous nuclei of the thalamus and hypothalamus, indicating that there are explicit targets for its action. In the thala-mus and hypothalamus a majority of neurons induced for c-fos expression also expressed the serotonin 5-HT7 re-ceptor, an allosteric target for Oleamide in in vitro studies. These data suggest that Oleamide may act at 5-HT7 receptors to elicit alterations in transcription that result in some of its physiological effects. Key Words: Oleam
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pharmacological activity of fatty acid amides is regulated but not mediated by fatty acid amide hydrolase in vivo
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Andrew H Lichtman, Gregory E Hawkins, Graeme Griffin, Benjamin F CravattAbstract:Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance Oleamide. Both anandamide and Oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, Oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of Oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(+/+) and (−/−) mice. In both genotypes, Oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(−/−) mice, were unaffected by the CB1 antagonist N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(−/−) mice. Additionally, Oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(+/+) or (−/−) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(−/−) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both Oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (−/−) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.
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The Endogenous Lipid Oleamide Activates Serotonin 5‐HT7 Neurons in Mouse Thalamus and Hypothalamus
Journal of neurochemistry, 2002Co-Authors: Elizabeth A. Thomas, Benjamin F Cravatt, J. Gregor SutcliffeAbstract:Abstract: Oleamide is an endogenous lipid that accumulates during sleep deprivation and has hypothermic effects when administered to rodents. The mechanisms for its activity remain unknown. Intraperitoneal injections of Oleamide elicited dramatic increases in content of c-fos mRNA and Fos protein in distinct brain regions, including cingulate and somatosensory cortical areas and numerous nuclei of the thalamus and hypothalamus, indicating that there are explicit targets for its action. In the thalamus and hypothalamus a majority of neurons induced for c-fos expression also expressed the serotonin 5-HT7 receptor, an allosteric target for Oleamide in in vitro studies. These data suggest that Oleamide may act at 5-HT7 receptors to elicit alterations in transcription that result in some of its physiological effects.
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Effect of Oleamide on sleep and its relationship to blood pressure, body temperature, and locomotor activity in rats.
Experimental neurology, 2001Co-Authors: Salvador Huitron-resendiz, Benjamin F Cravatt, Lhys M. Gombart, Steven J. HenriksenAbstract:Oleamide (cis-9,10-octadecenoamide) is a brain lipid that has recently been isolated from the cerebral fluid of sleep-deprived cats. Intracerebroventricular and intraperitoneal administration of Oleamide induces sleep in rats. However, it is unclear whether Oleamide's hypnogenic effects are mediated, in part, by its actions on blood pressure and core body temperature. Here we show that systemic administration of Oleamide (10 and 20 mg/kg) in rats increased slow-wave sleep 2, without affecting blood pressure and heart rate. In addition, Oleamide decreased body temperature and locomotor activity in a dose-dependent manner. These latter effects were not correlated in time with the observed increases in slow-wave sleep. These data suggest that the hypnogenic effects of Oleamide are not related to changes in blood pressure, heart rate, or body temperature.
Russell A. Nicholson - One of the best experts on this subject based on the ideXlab platform.
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the sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian cns in vitro
British Journal of Pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P<0.05) than GABA receptors (EC50, 22.12±1.4 μM; Maximum 171%±30, n=11). Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC50 from 322 to 239 μM: P<0.001). Modulation was not voltage-dependent or associated with a shift in Er. β1 containing GABAA receptors (insensitive to many depressant drugs) were positively modulated by Oleamide. Oleamide efficacy was circa 2× greater at α1β1γ2L than α1β2γ2L (P=0.007). Splice variation in γ subunits did not alter Oleamide sensitivity. cis-9,10-Octadecenoamide had no effect on the equilibrium binding of [3H]-muscimol or [3H]-EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid-, benzodiazepine- or barbiturate-like modulator of GABAA-receptors. The transport of [3H]-GABA into mouse brain synaptoneurosomes was unaffected by high micromolar concentrations of cis-9,10-octadecenoamide. Oleamide does not enhance GABA-ergic currents or prolong IPSCs by inhibiting GABA transport. Oleamide is a non-selective modulator of inhibitory ionotropic receptors. The sleep lipid exerts its effects indirectly, or at a novel recognition site on the GABAA complex. Keywords: cis-9,10-octadecenoamide/‘Oleamide' recombinant GABAA receptor, recombinant glycine receptor, human/rat brain receptors and ion channels, [3H]-EBOB and [3H]-muscimol binding, synaptoneurosomes, [3H]-GABA uptake Introduction The fatty acid amide, cis-9,10-octadecenoamide (‘Oleamide' or cOA), was isolated from the cerebrospinal fluid of sleep deprived cats, and synthetic cOA can induce sleep when injected i.p. or i.c.v. into naive animals (Cravatt et al., 1995; Basile et al., 1999). 5HT1, 2 and 7 receptors have been cited as high-affinity targets (Boger et al., 1998a) and 5HT receptors are certainly involved in sleep (Pascoe, 1994) but the concentration of Oleamide required to exert a maximal modulatory response in recombinant 5HT receptors (Huidobro Toro & Harris, 1996) is below the physiological range of Oleamide reported in the CSF of even alert animals (Basile et al., 1999). In contrast, at concentrations greater than 10 μM, Oleamide can uncouple gap junctions (Boger et al., 1998b). It has been suggested that cOA blocks gap junctions by increasing the membrane homeoviscosity of neurones (Lerner, 1997). Others suggest that although Oleamide (>10 μM) can fluidize membranes this is not relevant to sleep induction, but their ex vivo experiments suggest that sleep-inducing doses of the lipid result in very high brain concentrations (Gobbi et al., 1999). Oleamide is broken down by fatty acid amide hydrolase (FAAH) enzymes, which also degrade the endocannabinoid anandamide. Exogenous Oleamide's effects on locomotor activity (Cheer et al., 1999) and sleep are broadly cannabinomimetic (Mendelson & Basile, 1999). However, Oleamide binds only weakly to CB1 receptors (Cheer et al., 1999) and it cannot directly alter GTPγS binding (Boring et al., 1996). A popular interpretation of the above evidence is that Oleamide competes with anandamide for FAAH, causing the levels of anandamide to increase thus producing sleep (Cheer et al., 1999). We have highlighted that GABAA receptors (see also Yost et al., 1998) and voltage-gated sodium channels are both stereoselectively modulated by Oleamide (trans-Oleamide was much less potent as a sleep inducer and is not active at these presumptive targets in vitro) (Laws et al., 2001). Sodium channels are blocked by Oleamide in a state/voltage-dependent manner, which is an acknowledged effect of several classes of depressant drug (Verdon et al., 2000; Nicholson et al., 2001). GABAA receptor currents are enhanced in the presence of Oleamide (Lees et al., 1998). The modulatory effects of Oleamide on GABAA receptors, and the fact that it blocks voltage-gated sodium channels in a manner similar to anaesthetic and anticonvulsant drugs, suggests that this or related lipids may be endogenous ligands for drug recognition sites (Laws et al., 2001). Most anaesthetics (with the exception of ketamine, nitrous oxide and xenon) are demonstrably active at GABAA receptors, where their potency mirrors their anaesthetic potency in vivo (Franks & Lieb, 1994; Laws et al., 2001). Glycine receptors share sensitivity to a variety of anaesthetics and were an important tool in seeking key anaesthetic recognition domains on the GABAA receptor protein (Belelli et al., 1999b). The β subunit of the GABAA receptor and the α subunit of the glycine receptor contain sites on the M2 and M3 domains which are crucial for modulatory effects of depressant drugs. These sites confer sensitivity of the receptor not only to anaesthetics but also to the anticonvulsant loreclazole (Wafford et al., 1994) and the recently disclosed depressant effects of NSAIDS (Halliwell et al., 1999). Naturally occurring subunit combinations (isoforms) of the GABAA receptor show differing sensitivity to volatile anaesthetics, with the β1 containing receptors being insensitive. The β1 and β2 subunits contain different amino acid residues (β1, Ser-290, β2, Asn-289) in the M2 domain leading to the insensitivity of β1 to etomidate and loreclazole (Belelli et al., 1997). The M2 domain on both the α and β subunits confers absolute sensitivity to two volatile anaesthetics and ethanol (Mihic et al., 1997). A later publication by Krasowski & Harrison (2000) showed that 12 out of 13 general anaesthetics, including isoflurane and enflurane, had a reduced or no modulatory effect on GABA receptors containing mutations in the M2 domain of α and/or β subunits. This site on the M2 domain may represent a site for direct binding of Oleamide to the GABAA receptor although the GABAA receptor-chloride ion channel has a remarkable capacity for allosteric regulation by both drugs and steroid hormones. In this study we examine the sensitivity of glycine receptor subunits to modulation by Oleamide. Furthermore, we probe the influence of GABAA β subunits and of splice variation in γ subunits (which alter the sensitivity to ethanol) on Oleamide modulation. Biochemical experiments on GABA uptake and EBOB/muscimol binding are used to seek a mechanism for potentiation of chloride currents by Oleamide.
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The sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro
British journal of pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P
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Stereoselective modulatory actions of Oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS
British journal of pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, C Robin Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
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stereoselective modulatory actions of Oleamide on gabaa receptors and voltage gated na channels in vitro a putative endogenous ligand for depressant drug sites in cns
British Journal of Pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, Robin C Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
Jian Zheng - One of the best experts on this subject based on the ideXlab platform.
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the sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian cns in vitro
British Journal of Pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P<0.05) than GABA receptors (EC50, 22.12±1.4 μM; Maximum 171%±30, n=11). Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC50 from 322 to 239 μM: P<0.001). Modulation was not voltage-dependent or associated with a shift in Er. β1 containing GABAA receptors (insensitive to many depressant drugs) were positively modulated by Oleamide. Oleamide efficacy was circa 2× greater at α1β1γ2L than α1β2γ2L (P=0.007). Splice variation in γ subunits did not alter Oleamide sensitivity. cis-9,10-Octadecenoamide had no effect on the equilibrium binding of [3H]-muscimol or [3H]-EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid-, benzodiazepine- or barbiturate-like modulator of GABAA-receptors. The transport of [3H]-GABA into mouse brain synaptoneurosomes was unaffected by high micromolar concentrations of cis-9,10-octadecenoamide. Oleamide does not enhance GABA-ergic currents or prolong IPSCs by inhibiting GABA transport. Oleamide is a non-selective modulator of inhibitory ionotropic receptors. The sleep lipid exerts its effects indirectly, or at a novel recognition site on the GABAA complex. Keywords: cis-9,10-octadecenoamide/‘Oleamide' recombinant GABAA receptor, recombinant glycine receptor, human/rat brain receptors and ion channels, [3H]-EBOB and [3H]-muscimol binding, synaptoneurosomes, [3H]-GABA uptake Introduction The fatty acid amide, cis-9,10-octadecenoamide (‘Oleamide' or cOA), was isolated from the cerebrospinal fluid of sleep deprived cats, and synthetic cOA can induce sleep when injected i.p. or i.c.v. into naive animals (Cravatt et al., 1995; Basile et al., 1999). 5HT1, 2 and 7 receptors have been cited as high-affinity targets (Boger et al., 1998a) and 5HT receptors are certainly involved in sleep (Pascoe, 1994) but the concentration of Oleamide required to exert a maximal modulatory response in recombinant 5HT receptors (Huidobro Toro & Harris, 1996) is below the physiological range of Oleamide reported in the CSF of even alert animals (Basile et al., 1999). In contrast, at concentrations greater than 10 μM, Oleamide can uncouple gap junctions (Boger et al., 1998b). It has been suggested that cOA blocks gap junctions by increasing the membrane homeoviscosity of neurones (Lerner, 1997). Others suggest that although Oleamide (>10 μM) can fluidize membranes this is not relevant to sleep induction, but their ex vivo experiments suggest that sleep-inducing doses of the lipid result in very high brain concentrations (Gobbi et al., 1999). Oleamide is broken down by fatty acid amide hydrolase (FAAH) enzymes, which also degrade the endocannabinoid anandamide. Exogenous Oleamide's effects on locomotor activity (Cheer et al., 1999) and sleep are broadly cannabinomimetic (Mendelson & Basile, 1999). However, Oleamide binds only weakly to CB1 receptors (Cheer et al., 1999) and it cannot directly alter GTPγS binding (Boring et al., 1996). A popular interpretation of the above evidence is that Oleamide competes with anandamide for FAAH, causing the levels of anandamide to increase thus producing sleep (Cheer et al., 1999). We have highlighted that GABAA receptors (see also Yost et al., 1998) and voltage-gated sodium channels are both stereoselectively modulated by Oleamide (trans-Oleamide was much less potent as a sleep inducer and is not active at these presumptive targets in vitro) (Laws et al., 2001). Sodium channels are blocked by Oleamide in a state/voltage-dependent manner, which is an acknowledged effect of several classes of depressant drug (Verdon et al., 2000; Nicholson et al., 2001). GABAA receptor currents are enhanced in the presence of Oleamide (Lees et al., 1998). The modulatory effects of Oleamide on GABAA receptors, and the fact that it blocks voltage-gated sodium channels in a manner similar to anaesthetic and anticonvulsant drugs, suggests that this or related lipids may be endogenous ligands for drug recognition sites (Laws et al., 2001). Most anaesthetics (with the exception of ketamine, nitrous oxide and xenon) are demonstrably active at GABAA receptors, where their potency mirrors their anaesthetic potency in vivo (Franks & Lieb, 1994; Laws et al., 2001). Glycine receptors share sensitivity to a variety of anaesthetics and were an important tool in seeking key anaesthetic recognition domains on the GABAA receptor protein (Belelli et al., 1999b). The β subunit of the GABAA receptor and the α subunit of the glycine receptor contain sites on the M2 and M3 domains which are crucial for modulatory effects of depressant drugs. These sites confer sensitivity of the receptor not only to anaesthetics but also to the anticonvulsant loreclazole (Wafford et al., 1994) and the recently disclosed depressant effects of NSAIDS (Halliwell et al., 1999). Naturally occurring subunit combinations (isoforms) of the GABAA receptor show differing sensitivity to volatile anaesthetics, with the β1 containing receptors being insensitive. The β1 and β2 subunits contain different amino acid residues (β1, Ser-290, β2, Asn-289) in the M2 domain leading to the insensitivity of β1 to etomidate and loreclazole (Belelli et al., 1997). The M2 domain on both the α and β subunits confers absolute sensitivity to two volatile anaesthetics and ethanol (Mihic et al., 1997). A later publication by Krasowski & Harrison (2000) showed that 12 out of 13 general anaesthetics, including isoflurane and enflurane, had a reduced or no modulatory effect on GABA receptors containing mutations in the M2 domain of α and/or β subunits. This site on the M2 domain may represent a site for direct binding of Oleamide to the GABAA receptor although the GABAA receptor-chloride ion channel has a remarkable capacity for allosteric regulation by both drugs and steroid hormones. In this study we examine the sensitivity of glycine receptor subunits to modulation by Oleamide. Furthermore, we probe the influence of GABAA β subunits and of splice variation in γ subunits (which alter the sensitivity to ethanol) on Oleamide modulation. Biochemical experiments on GABA uptake and EBOB/muscimol binding are used to seek a mechanism for potentiation of chloride currents by Oleamide.
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The sleep hormone Oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro
British journal of pharmacology, 2002Co-Authors: Leanne Coyne, Jian Zheng, Russell A. Nicholson, George Lees, Katherine D NeufieldAbstract:We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to Oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo-oligomers (significant), was less marked, with a lower EC50 (P
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Stereoselective modulatory actions of Oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS
British journal of pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, C Robin Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
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stereoselective modulatory actions of Oleamide on gabaa receptors and voltage gated na channels in vitro a putative endogenous ligand for depressant drug sites in cns
British Journal of Pharmacology, 2000Co-Authors: Bernard Verdon, Jian Zheng, Russell A. Nicholson, Robin C Ganelli, George LeesAbstract:1. cis-9,10-octadecenoamide ('Oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-Oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-Oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-Oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-Oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.
Makoto Ushimaru - One of the best experts on this subject based on the ideXlab platform.
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inhibitory action of linOleamide and Oleamide toward sarco endoplasmic reticulum ca2 atpase
Biochimica et Biophysica Acta, 2017Co-Authors: Sachiko Yamamoto, Munenori Takehara, Makoto UshimaruAbstract:Abstract Background SERCA maintains intracellular Ca 2+ homeostasis by sequestering cytosolic Ca 2+ into SR/ER stores. Two primary fatty acid amides (PFAAs), Oleamide (18:1 9- cis ) and linOleamide (18:2 9,12- cis ), induce an increase in intracellular Ca 2+ levels, which might be caused by their inhibition of SERCA. Methods Three major SERCA isoforms, rSERCA1a, hSERCA2b, and hSERCA3a, were individually overexpressed in COS-1 cells, and the inhibitory action of PFAAs on Ca 2+ -ATPase activity of SERCA was examined. Results The Ca 2+ -ATPase activity of each SERCA was inhibited in a concentration-dependent manner strongly by linOleamide (IC 50 15–53 μM) and partially by Oleamide (IC 50 8.3–34 μM). Inhibition by other PFAAs, such as stearamide (18:0) and elaidamide (18:1 9- trans ), was hardly or slightly observed. With increasing dose, linOleamide decreased the apparent affinity for Ca 2+ and the apparent maximum velocity of Ca 2+ -ATPase activity of all SERCAs tested. Oleamide also lowered these values for hSERCA3a. Meanwhile, Oleamide uniquely reduced the apparent Ca 2+ affinity of rSERCA1a and hSERCA2b: the reduction was considerably attenuated above certain concentrations of Oleamide. The dissociation constants for SERCA interaction varied from 6 to 45 μM in linOleamide and from 1.6 to 55 μM in Oleamide depending on the isoform. Conclusions LinOleamide and Oleamide inhibit SERCA activity in the micromolar concentration range, and in a different manner. Both amides mainly suppress SERCA activity by lowering the Ca 2+ affinity of the enzyme. General significance Our findings imply a novel role of these PFAAs as modulators of intracellular Ca 2+ homeostasis via regulation of SERCA activity.
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Inhibitory action of linOleamide and Oleamide toward sarco/endoplasmic reticulum Ca2+-ATPase.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2017Co-Authors: Sachiko Yamamoto, Munenori Takehara, Makoto UshimaruAbstract:Abstract Background SERCA maintains intracellular Ca 2+ homeostasis by sequestering cytosolic Ca 2+ into SR/ER stores. Two primary fatty acid amides (PFAAs), Oleamide (18:1 9- cis ) and linOleamide (18:2 9,12- cis ), induce an increase in intracellular Ca 2+ levels, which might be caused by their inhibition of SERCA. Methods Three major SERCA isoforms, rSERCA1a, hSERCA2b, and hSERCA3a, were individually overexpressed in COS-1 cells, and the inhibitory action of PFAAs on Ca 2+ -ATPase activity of SERCA was examined. Results The Ca 2+ -ATPase activity of each SERCA was inhibited in a concentration-dependent manner strongly by linOleamide (IC 50 15–53 μM) and partially by Oleamide (IC 50 8.3–34 μM). Inhibition by other PFAAs, such as stearamide (18:0) and elaidamide (18:1 9- trans ), was hardly or slightly observed. With increasing dose, linOleamide decreased the apparent affinity for Ca 2+ and the apparent maximum velocity of Ca 2+ -ATPase activity of all SERCAs tested. Oleamide also lowered these values for hSERCA3a. Meanwhile, Oleamide uniquely reduced the apparent Ca 2+ affinity of rSERCA1a and hSERCA2b: the reduction was considerably attenuated above certain concentrations of Oleamide. The dissociation constants for SERCA interaction varied from 6 to 45 μM in linOleamide and from 1.6 to 55 μM in Oleamide depending on the isoform. Conclusions LinOleamide and Oleamide inhibit SERCA activity in the micromolar concentration range, and in a different manner. Both amides mainly suppress SERCA activity by lowering the Ca 2+ affinity of the enzyme. General significance Our findings imply a novel role of these PFAAs as modulators of intracellular Ca 2+ homeostasis via regulation of SERCA activity.
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Inhibitory action of linOleamide and Oleamide toward sarco/endoplasmic reticulum Ca2+-ATPase.
Biochimica et biophysica acta. General subjects, 2016Co-Authors: Sachiko Yamamoto, Munenori Takehara, Makoto UshimaruAbstract:SERCA maintains intracellular Ca2+ homeostasis by sequestering cytosolic Ca2+ into SR/ER stores. Two primary fatty acid amides (PFAAs), Oleamide (18:19-cis) and linOleamide (18:29,12-cis), induce an increase in intracellular Ca2+ levels, which might be caused by their inhibition of SERCA. Three major SERCA isoforms, rSERCA1a, hSERCA2b, and hSERCA3a, were individually overexpressed in COS-1 cells, and the inhibitory action of PFAAs on Ca2+-ATPase activity of SERCA was examined. The Ca2+-ATPase activity of each SERCA was inhibited in a concentration-dependent manner strongly by linOleamide (IC50 15-53μM) and partially by Oleamide (IC50 8.3-34μM). Inhibition by other PFAAs, such as stearamide (18:0) and elaidamide (18:19-trans), was hardly or slightly observed. With increasing dose, linOleamide decreased the apparent affinity for Ca2+ and the apparent maximum velocity of Ca2+-ATPase activity of all SERCAs tested. Oleamide also lowered these values for hSERCA3a. Meanwhile, Oleamide uniquely reduced the apparent Ca2+ affinity of rSERCA1a and hSERCA2b: the reduction was considerably attenuated above certain concentrations of Oleamide. The dissociation constants for SERCA interaction varied from 6 to 45μM in linOleamide and from 1.6 to 55μM in Oleamide depending on the isoform. LinOleamide and Oleamide inhibit SERCA activity in the micromolar concentration range, and in a different manner. Both amides mainly suppress SERCA activity by lowering the Ca2+ affinity of the enzyme. Our findings imply a novel role of these PFAAs as modulators of intracellular Ca2+ homeostasis via regulation of SERCA activity. Copyright © 2016 Elsevier B.V. All rights reserved.
