The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Kunihiko Yokotani - One of the best experts on this subject based on the ideXlab platform.
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brain phosphoLipase c Diacylglycerol Lipase and monoacylglycerol Lipase are involved in epibatidine induced activation of central adrenomedullary outflow in rats
European Journal of Pharmacology, 2012Co-Authors: Takahiro Shimizu, Kenjiro Tanaka, Kumiko Nakamura, Keisuke Taniuchi, Kunihiko YokotaniAbstract:Abstract We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (a potent agonist of nicotinic acetylcholine receptors) (1, 5 and 10 nmol/animal) dose-dependently elevated plasma levels of noradrenaline and adrenaline and that this response was reduced by i.c.v. administered indomethacin (cyclooxygenase inhibitor) and abolished by bilateral adrenalectomy, indicating the involvement of brain arachidonic acid, as a substrate of cyclooxygenase, in this alkaloid-induced secretion of both catecholamines from the adrenal medulla in rats. Arachidonic acid is mainly released by the action of phosphoLipase A2, but is also released by a phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway. In the present study, (±)-epibatidine (5 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was not influenced by pretreatment with mepacrine (phosphoLipase A2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.), but was effectively reduced by pretreatment with U-73122 (1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (phosphoLipase C inhibitor) (10 and 30 nmol/animal, i.c.v.), RHC-80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.), MAFP (methyl arachidonoyl fluorophosphonate) (monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.) or JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (selective monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activates spinally projecting neurons expressing monoacylglycerol Lipase in the rat hypothalamic paraventricular nucleus, a control center of central sympatho-adrenomedullary outflow. Taken together, the brain phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway seems to be involved in the centrally administered (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
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Brain phosphoLipase C, Diacylglycerol Lipase and monoacylglycerol Lipase are involved in (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
European journal of pharmacology, 2012Co-Authors: Takahiro Shimizu, Kenjiro Tanaka, Kumiko Nakamura, Keisuke Taniuchi, Kunihiko YokotaniAbstract:We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (a potent agonist of nicotinic acetylcholine receptors) (1, 5 and 10 nmol/animal) dose-dependently elevated plasma levels of noradrenaline and adrenaline and that this response was reduced by i.c.v. administered indomethacin (cyclooxygenase inhibitor) and abolished by bilateral adrenalectomy, indicating the involvement of brain arachidonic acid, as a substrate of cyclooxygenase, in this alkaloid-induced secretion of both catecholamines from the adrenal medulla in rats. Arachidonic acid is mainly released by the action of phosphoLipase A(2), but is also released by a phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway. In the present study, (±)-epibatidine (5 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was not influenced by pretreatment with mepacrine (phosphoLipase A(2) inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.), but was effectively reduced by pretreatment with U-73122 (1-[6-[[(17 β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (phosphoLipase C inhibitor) (10 and 30 nmol/animal, i.c.v.), RHC-80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.), MAFP (methyl arachidonoyl fluorophosphonate) (monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.) or JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (selective monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activates spinally projecting neurons expressing monoacylglycerol Lipase in the rat hypothalamic paraventricular nucleus, a control center of central sympatho-adrenomedullary outflow. Taken together, the brain phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway seems to be involved in the centrally administered (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
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roles of brain phosphatidylinositol specific phosphoLipase c and Diacylglycerol Lipase in centrally administered histamine induced adrenomedullary outflow in rats
European Journal of Pharmacology, 2007Co-Authors: Takahiro Shimizu, Naoko Yamaguchi, Shoshiro Okada, Lianyi Lu, Tsuyoshi Sasaki, Kunihiko YokotaniAbstract:Abstract Recently, we reported that intracerebroventricularly (i.c.v.) administered histamine evokes the secretion of noradrenaline and adrenaline from adrenal medulla by brain cyclooxygenase-1- and thromboxane A2-mediated mechanisms in rats. These results suggest the involvement of brain arachidonic acid cascade in the histamine-induced activation of the central adrenomedullary outflow. Arachidonic acid is released mainly by phosphoLipase A2 (PLA2)-dependent pathway or phosphoLipase C (PLC)/Diacylglycerol Lipase-dependent pathway. In the present study, histamine (27 nmol/animal, i.c.v.) -induced elevation of plasma noradrenaline and adrenaline was dose-dependently reduced by U-73122 (PLC inhibitor) (10 and 100 nmol/animal, i.c.v.), ET-18-OCH3 (phosphatidylinositol-specific PLC inhibitor) (10 and 30 nmol/animal, i.c.v.) and RHC-80267 (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.). However, mepacrine (PLA2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.) and D609 (phosphatidylcholine-specific PLC inhibitor) (30, 100 and 300 nmol/animal, i.c.v.) had no effect. These results suggest the involvement of brain phosphatidylinositol-specific PLC and Diacylglycerol Lipase in the centrally administered histamine-induced activation of the adrenomedullary outflow in rats.
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brain phosphoLipase c Diacylglycerol Lipase are involved in bombesin bb2 receptor mediated activation of sympatho adrenomedullary outflow in rats
European Journal of Pharmacology, 2005Co-Authors: Takahiro Shimizu, Naoko Yamaguchi, Shoshiro Okada, Junichi Arai, Hiroshi Wakiguchi, Kunihiko YokotaniAbstract:Abstract Bombesin receptors are mainly divided into two subtypes: BB 1 receptor (neuromedin B-preferring receptor) and BB 2 receptor [gastrin-releasing peptide (GRP)-preferring receptor]. Previously, we reported that intracerebroventricularly (i.c.v.) administered bombesin elevates plasma noradrenaline and adrenaline by production of brain arachidonic acid in rats. Arachidonic acid is released mainly by phosphoLipase A 2 (PLA 2 )-dependent pathway or phosphoLipase C (PLC)/Diacylglycerol Lipase-dependent pathway. In the present study, bombesin and GRP elevated plasma catecholamines in a dose-dependent manner (1 and 5 nmol/animal, i.c.v.), while neuromedin B (1, 5 and 10 nmol/animal, i.c.v.) had no effect in urethane-anesthetized rats (bombesin = GRP ≫ neuromedin B). The bombesin (1 nmol/animal, i.c.v.)-induced response was dose-dependently attenuated by [ d -Phe 6 , des-Met 14 ]-bombesin (6–14) ethylamide (bombesin BB 2 receptor antagonist) (15.3 and 30.6 nmol/animal, i.c.v.) and also by U-73122 (PLC inhibitor) (10 and 100 nmol/animal, i.c.v.) and RHC-80267 (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.). However, d -Nal-cyclo[Cys-Tyr- d -Trp-Orn-Val-Cys]-Nal-NH 2 (bombesin BB 1 receptor antagonist) (30 and 100 nmol/animal, i.c.v.), mepacrine (PLA 2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.) and U-73343 (inactive analog of U-73122) (100 nmol/animal, i.c.v.) had no effect. These results suggest the involvement of brain PLC/Diacylglycerol Lipase in the brain bombesin BB 2 receptor-mediated activation of sympatho-adrenomedullary outflow in rats.
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brain phosphoLipase c Diacylglycerol Lipase pathway is involved in vasopressin induced release of noradrenaline and adrenaline from adrenal medulla in rats
European Journal of Pharmacology, 2004Co-Authors: Takahiro Shimizu, Shoshiro Okada, Naoko Yamaguchishima, Kunihiko YokotaniAbstract:Abstract Recently, we reported that intracerebroventricularly (i.c.v.) administered arginine–vasopressin evokes the release of noradrenaline and adrenaline from adrenal medulla by brain thromboxane A2-mediated mechanisms in rats. These results suggest the involvement of brain arachidonic acid in the vasopressin-induced activation of the central adrenomedullary outflow. Arachidonic acid is released mainly by two pathways: phosphoLipase A2 (PLA2)-dependent pathway; phosphoLipase C (PLC)- and Diacylglycerol Lipase-dependent pathway. In the present study, therefore, we attempted to identify which pathway is involved in the vasopressin-induced release of both catecholamines from adrenal medulla using urethane-anesthetized rats. Vasopressin (0.2 nmol/animal, i.c.v.)-induced elevation of plasma noradrenaline and adrenaline was dose-dependently reduced by neomycin [0.28 and 0.55 μmol (250 and 500 μg)/animal, i.c.v.] and 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122) [5 and 10 nmol (2.3 and 4.6 μg)/animal, i.c.v.] (inhibitors of PLC), and also by 1,6-bis(cyclohexyloximinocarbonylamino)hexane (RHC-80267) [1.3 and 2.6 μmol (500 and 1000 μg)/animal, i.c.v.] (an inhibitor of Diacylglycerol Lipase). On the other hand, mepacrine [1.1 and 2.2 μmol (500 and 1000 μg)/animal, i.c.v.] (an inhibitor of PLA2) was largely ineffective on the vasopressin-induced elevation of plasma catecholamines. These results suggest that vasopressin evokes the release of noradrenaline and adrenaline from adrenal medulla by the brain PLC- and Diacylglycerol Lipase-dependent mechanisms in rats.
Takahiro Shimizu - One of the best experts on this subject based on the ideXlab platform.
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brain phosphoLipase c Diacylglycerol Lipase and monoacylglycerol Lipase are involved in epibatidine induced activation of central adrenomedullary outflow in rats
European Journal of Pharmacology, 2012Co-Authors: Takahiro Shimizu, Kenjiro Tanaka, Kumiko Nakamura, Keisuke Taniuchi, Kunihiko YokotaniAbstract:Abstract We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (a potent agonist of nicotinic acetylcholine receptors) (1, 5 and 10 nmol/animal) dose-dependently elevated plasma levels of noradrenaline and adrenaline and that this response was reduced by i.c.v. administered indomethacin (cyclooxygenase inhibitor) and abolished by bilateral adrenalectomy, indicating the involvement of brain arachidonic acid, as a substrate of cyclooxygenase, in this alkaloid-induced secretion of both catecholamines from the adrenal medulla in rats. Arachidonic acid is mainly released by the action of phosphoLipase A2, but is also released by a phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway. In the present study, (±)-epibatidine (5 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was not influenced by pretreatment with mepacrine (phosphoLipase A2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.), but was effectively reduced by pretreatment with U-73122 (1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (phosphoLipase C inhibitor) (10 and 30 nmol/animal, i.c.v.), RHC-80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.), MAFP (methyl arachidonoyl fluorophosphonate) (monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.) or JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (selective monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activates spinally projecting neurons expressing monoacylglycerol Lipase in the rat hypothalamic paraventricular nucleus, a control center of central sympatho-adrenomedullary outflow. Taken together, the brain phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway seems to be involved in the centrally administered (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
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Brain phosphoLipase C, Diacylglycerol Lipase and monoacylglycerol Lipase are involved in (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
European journal of pharmacology, 2012Co-Authors: Takahiro Shimizu, Kenjiro Tanaka, Kumiko Nakamura, Keisuke Taniuchi, Kunihiko YokotaniAbstract:We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (a potent agonist of nicotinic acetylcholine receptors) (1, 5 and 10 nmol/animal) dose-dependently elevated plasma levels of noradrenaline and adrenaline and that this response was reduced by i.c.v. administered indomethacin (cyclooxygenase inhibitor) and abolished by bilateral adrenalectomy, indicating the involvement of brain arachidonic acid, as a substrate of cyclooxygenase, in this alkaloid-induced secretion of both catecholamines from the adrenal medulla in rats. Arachidonic acid is mainly released by the action of phosphoLipase A(2), but is also released by a phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway. In the present study, (±)-epibatidine (5 nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was not influenced by pretreatment with mepacrine (phosphoLipase A(2) inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.), but was effectively reduced by pretreatment with U-73122 (1-[6-[[(17 β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (phosphoLipase C inhibitor) (10 and 30 nmol/animal, i.c.v.), RHC-80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.), MAFP (methyl arachidonoyl fluorophosphonate) (monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.) or JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (selective monoacylglycerol Lipase inhibitor) (0.7 and 1.4 μmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activates spinally projecting neurons expressing monoacylglycerol Lipase in the rat hypothalamic paraventricular nucleus, a control center of central sympatho-adrenomedullary outflow. Taken together, the brain phosphoLipase C-, Diacylglycerol Lipase- and monoacylglycerol Lipase-mediated pathway seems to be involved in the centrally administered (±)-epibatidine-induced activation of central adrenomedullary outflow in rats.
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roles of brain phosphatidylinositol specific phosphoLipase c and Diacylglycerol Lipase in centrally administered histamine induced adrenomedullary outflow in rats
European Journal of Pharmacology, 2007Co-Authors: Takahiro Shimizu, Naoko Yamaguchi, Shoshiro Okada, Lianyi Lu, Tsuyoshi Sasaki, Kunihiko YokotaniAbstract:Abstract Recently, we reported that intracerebroventricularly (i.c.v.) administered histamine evokes the secretion of noradrenaline and adrenaline from adrenal medulla by brain cyclooxygenase-1- and thromboxane A2-mediated mechanisms in rats. These results suggest the involvement of brain arachidonic acid cascade in the histamine-induced activation of the central adrenomedullary outflow. Arachidonic acid is released mainly by phosphoLipase A2 (PLA2)-dependent pathway or phosphoLipase C (PLC)/Diacylglycerol Lipase-dependent pathway. In the present study, histamine (27 nmol/animal, i.c.v.) -induced elevation of plasma noradrenaline and adrenaline was dose-dependently reduced by U-73122 (PLC inhibitor) (10 and 100 nmol/animal, i.c.v.), ET-18-OCH3 (phosphatidylinositol-specific PLC inhibitor) (10 and 30 nmol/animal, i.c.v.) and RHC-80267 (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.). However, mepacrine (PLA2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.) and D609 (phosphatidylcholine-specific PLC inhibitor) (30, 100 and 300 nmol/animal, i.c.v.) had no effect. These results suggest the involvement of brain phosphatidylinositol-specific PLC and Diacylglycerol Lipase in the centrally administered histamine-induced activation of the adrenomedullary outflow in rats.
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brain phosphoLipase c Diacylglycerol Lipase are involved in bombesin bb2 receptor mediated activation of sympatho adrenomedullary outflow in rats
European Journal of Pharmacology, 2005Co-Authors: Takahiro Shimizu, Naoko Yamaguchi, Shoshiro Okada, Junichi Arai, Hiroshi Wakiguchi, Kunihiko YokotaniAbstract:Abstract Bombesin receptors are mainly divided into two subtypes: BB 1 receptor (neuromedin B-preferring receptor) and BB 2 receptor [gastrin-releasing peptide (GRP)-preferring receptor]. Previously, we reported that intracerebroventricularly (i.c.v.) administered bombesin elevates plasma noradrenaline and adrenaline by production of brain arachidonic acid in rats. Arachidonic acid is released mainly by phosphoLipase A 2 (PLA 2 )-dependent pathway or phosphoLipase C (PLC)/Diacylglycerol Lipase-dependent pathway. In the present study, bombesin and GRP elevated plasma catecholamines in a dose-dependent manner (1 and 5 nmol/animal, i.c.v.), while neuromedin B (1, 5 and 10 nmol/animal, i.c.v.) had no effect in urethane-anesthetized rats (bombesin = GRP ≫ neuromedin B). The bombesin (1 nmol/animal, i.c.v.)-induced response was dose-dependently attenuated by [ d -Phe 6 , des-Met 14 ]-bombesin (6–14) ethylamide (bombesin BB 2 receptor antagonist) (15.3 and 30.6 nmol/animal, i.c.v.) and also by U-73122 (PLC inhibitor) (10 and 100 nmol/animal, i.c.v.) and RHC-80267 (Diacylglycerol Lipase inhibitor) (1.3 and 2.6 μmol/animal, i.c.v.). However, d -Nal-cyclo[Cys-Tyr- d -Trp-Orn-Val-Cys]-Nal-NH 2 (bombesin BB 1 receptor antagonist) (30 and 100 nmol/animal, i.c.v.), mepacrine (PLA 2 inhibitor) (1.1 and 2.2 μmol/animal, i.c.v.) and U-73343 (inactive analog of U-73122) (100 nmol/animal, i.c.v.) had no effect. These results suggest the involvement of brain PLC/Diacylglycerol Lipase in the brain bombesin BB 2 receptor-mediated activation of sympatho-adrenomedullary outflow in rats.
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brain phosphoLipase c Diacylglycerol Lipase pathway is involved in vasopressin induced release of noradrenaline and adrenaline from adrenal medulla in rats
European Journal of Pharmacology, 2004Co-Authors: Takahiro Shimizu, Shoshiro Okada, Naoko Yamaguchishima, Kunihiko YokotaniAbstract:Abstract Recently, we reported that intracerebroventricularly (i.c.v.) administered arginine–vasopressin evokes the release of noradrenaline and adrenaline from adrenal medulla by brain thromboxane A2-mediated mechanisms in rats. These results suggest the involvement of brain arachidonic acid in the vasopressin-induced activation of the central adrenomedullary outflow. Arachidonic acid is released mainly by two pathways: phosphoLipase A2 (PLA2)-dependent pathway; phosphoLipase C (PLC)- and Diacylglycerol Lipase-dependent pathway. In the present study, therefore, we attempted to identify which pathway is involved in the vasopressin-induced release of both catecholamines from adrenal medulla using urethane-anesthetized rats. Vasopressin (0.2 nmol/animal, i.c.v.)-induced elevation of plasma noradrenaline and adrenaline was dose-dependently reduced by neomycin [0.28 and 0.55 μmol (250 and 500 μg)/animal, i.c.v.] and 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122) [5 and 10 nmol (2.3 and 4.6 μg)/animal, i.c.v.] (inhibitors of PLC), and also by 1,6-bis(cyclohexyloximinocarbonylamino)hexane (RHC-80267) [1.3 and 2.6 μmol (500 and 1000 μg)/animal, i.c.v.] (an inhibitor of Diacylglycerol Lipase). On the other hand, mepacrine [1.1 and 2.2 μmol (500 and 1000 μg)/animal, i.c.v.] (an inhibitor of PLA2) was largely ineffective on the vasopressin-induced elevation of plasma catecholamines. These results suggest that vasopressin evokes the release of noradrenaline and adrenaline from adrenal medulla by the brain PLC- and Diacylglycerol Lipase-dependent mechanisms in rats.
Masahiko Watanabe - One of the best experts on this subject based on the ideXlab platform.
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Diacylglycerol Lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
Scientific Reports, 2013Co-Authors: Erik Keimpema, Fiona V Howell, Masahiko Watanabe, Carl Hobbs, Alan Alpar, Katarzyna Malenczyk, Yasmin L Hurd, Kenji Sakimura, Masanobu KanoAbstract:Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-Diacylglycerol Lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB1 cannabinoid receptors (CB1Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLα null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLα overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB1R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB1Rs along discrete spherical boundaries to modulate neuronal responsiveness.
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activation of type 5 metabotropic glutamate receptors and Diacylglycerol Lipase α initiates 2 arachidonoylglycerol formation and endocannabinoid mediated analgesia
The Journal of Neuroscience, 2012Co-Authors: Laura C Gregg, Ken Mackie, Masahiko Watanabe, Kwangmook Jung, Jessica M Spradley, Rita Nyilas, Richard L Suplita, Andreas Zimmer, Istvan Katona, Daniele PiomelliAbstract:Acute stress reduces pain sensitivity by engaging an endocannabinoid signaling circuit in the midbrain. The neural mechanisms governing this process and molecular identity of the endocannabinoid substance(s) involved are unknown. We combined behavior, pharmacology, immunohistochemistry, RNA interference, quantitative RT-PCR, enzyme assays, and lipidomic analyses of endocannabinoid content to uncover the role of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in controlling pain sensitivity in vivo. Here, we show that footshock stress produces antinociception in rats by activating type 5 metabotropic glutamate receptors (mGlu5) in the dorsolateral periaqueductal gray (dlPAG) and mobilizing 2-AG. Stimulation of mGlu5 in the dlPAG with DHPG [(S)-3,5-dihydroxyphenylglycine] triggered 2-AG formation and enhanced stress-dependent antinociception through a mechanism dependent upon both postsynaptic Diacylglycerol Lipase (DGL) activity, which releases 2-AG, and presynaptic CB1 cannabinoid receptors. Pharmacological blockade of DGL activity in the dlPAG with RHC80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] and (−)-tetrahydrolipstatin (THL), which inhibit activity of DGL-α and DGL-β isoforms, suppressed stress-induced antinociception. Inhibition of DGL activity in the dlPAG with THL selectively decreased accumulation of 2-AG without altering levels of anandamide. The putative 2-AG-synthesizing enzyme DGL-α colocalized with mGlu5 at postsynaptic sites of the dlPAG, whereas CB1 was confined to presynaptic terminals, consistent with a role for 2-AG as a retrograde signaling messenger. Finally, virally mediated silencing of DGL-α, but not DGL-β, transcription in the dlPAG mimicked effects of DGL inhibition in suppressing both endocannabinoid-mediated stress antinociception and 2-AG formation. The results indicate that activation of the postsynaptic mGlu5–DGL-α cascade triggers retrograde 2-AG signaling in vivo. This pathway is required for endocannabinoid-mediated stress-induced analgesia.
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the endocannabinoid 2 arachidonoylglycerol produced by Diacylglycerol Lipase α mediates retrograde suppression of synaptic transmission
Neuron, 2010Co-Authors: Asami Tanimura, Maya Yamazaki, Yuki Hashimotodani, Motokazu Uchigashima, Shinya Kawata, Yoshihiro Kita, Kouichi Hashimoto, Takao Shimizu, Masahiko WatanabeAbstract:Summary Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes Diacylglycerol Lipase α (DGLα) and β (DGLβ). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLα knockout brains, whereas the 2-AG content was normal in DGLβ knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLα, but not by DGLβ, mediates retrograde suppression at central synapses.
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localization of Diacylglycerol Lipase alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid 2 arachidonoyl glycerol and presynaptic cannabinoid cb1 receptor
The Journal of Neuroscience, 2006Co-Authors: Takayuki Yoshida, Motokazu Uchigashima, Masanobu Kano, Masahiro Fukaya, Eriko Miura, Haruyuki Kamiya, Masahiko WatanabeAbstract:2-Arachidonoyl-glycerol (2-AG) is an endocannabinoid that is released from postsynaptic neurons, acts retrogradely on presynaptic cannabinoid receptor CB1, and induces short- and long-term suppression of transmitter release. To understand the mechanisms of the 2-AG-mediated retrograde modulation, we investigated subcellular localization of a major 2-AG biosynthetic enzyme, Diacylglycerol Lipase-α (DAGLα), by using immunofluorescence and immunoelectron microscopy in the mouse brain. In the cerebellum, DAGLα was predominantly expressed in Purkinje cells. DAGLα was detected on the dendritic surface and occasionally on the somatic surface, with a distal-to-proximal gradient from spiny branchlets toward somata. DAGLα was highly concentrated at the base of spine neck and also accumulated with much lower density on somatodendritic membrane around the spine neck. However, DAGLα was excluded from the main body of spine neck and head. In hippocampal pyramidal cells, DAGLα was also accumulated in spines. In contrast to the distribution in Purkinje cells, DAGLα was distributed in the spine head, neck, or both, whereas somatodendritic membrane was labeled very weakly. These results indicate that DAGLα is essentially targeted to postsynaptic spines in cerebellar and hippocampal neurons, but its fine distribution within and around spines is differently regulated between the two neurons. The preferential spine targeting should enable efficient 2-AG production on excitatory synaptic activity and its swift retrograde modulation onto nearby presynaptic terminals expressing CB1. Furthermore, different fine localization within and around spines suggests that the distance between postsynaptic 2-AG production site and presynaptic CB1 is differentially controlled depending on neuron types.
Vincenzo Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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palmitoylethanolamide counteracts substance p induced mast cell activation in vitro by stimulating Diacylglycerol Lipase activity
Journal of Neuroinflammation, 2019Co-Authors: Stefania Petrosino, Marco Allara, Alessia Ligresti, Aniello Schiano Moriello, Roberta Verde, Roberta Imperatore, Ali Mokhtar Mahmoud, Alessio Filippo Peritore, Fabio Arturo Iannotti, Vincenzo Di MarzoAbstract:Palmitoylethanolamide (PEA) is a pleiotropic endogenous lipid mediator currently used as a “dietary food for special medical purposes” against neuropathic pain and neuro-inflammatory conditions. Several mechanisms underlie PEA actions, among which the “entourage” effect, consisting of PEA potentiation of endocannabinoid signaling at either cannabinoid receptors or transient receptor potential vanilloid type-1 (TRPV1) channels. Here, we report novel molecular mechanisms through which PEA controls mast cell degranulation and substance P (SP)-induced histamine release in rat basophilic leukemia (RBL-2H3) cells, a mast cell model. RBL-2H3 cells stimulated with SP were treated with PEA in the presence and absence of a cannabinoid type-2 (CB2) receptor antagonist (AM630), or a Diacylglycerol Lipase (DAGL) enzyme inhibitor (OMDM188) to inhibit the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The release of histamine was measured by ELISA and β-hexosaminidase release and toluidine blue staining were used as indices of degranulation. 2-AG levels were measured by LC-MS. The mRNA expression of proposed PEA targets (Cnr1, Cnr2, Trpv1, Ppara and Gpr55), and of PEA and endocannabinoid biosynthetic (Napepld, Dagla and Daglb) and catabolic (Faah, Naaa and Mgl) enzymes were also measured. The effects of PEA on the activity of DAGL-α or -β enzymes were assessed in COS-7 cells overexpressing the human recombinant enzyme or in RBL-2H3 cells, respectively. SP increased the number of degranulated RBL-2H3 cells and triggered the release of histamine. PEA counteracted these effects in a manner antagonized by AM630. PEA concomitantly increased the levels of 2-AG in SP-stimulated RBL-2H3 cells, and this effect was reversed by OMDM188. PEA significantly stimulated DAGL-α and -β activity and, consequently, 2-AG biosynthesis in cell-free systems. Co-treatment with PEA and 2-AG at per se ineffective concentrations downmodulated SP-induced release of histamine and degranulation, and this effect was reversed by OMDM188. Activation of CB2 underlies the inhibitory effects on SP-induced RBL-2H3 cell degranulation by PEA alone. We demonstrate for the first time that the effects in RBL-2H3 cells of PEA are due to the stimulation of 2-AG biosynthesis by DAGLs.
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discovery of glycine sulfonamides as dual inhibitors of sn 1 Diacylglycerol Lipase α and α β hydrolase domain 6
Journal of Medicinal Chemistry, 2014Co-Authors: Freek J Janssen, Marc P Baggelaar, Hui Deng, Hans Den Dulk, Marco Allara, Vincenzo Di Marzo, Alessia Ligresti, Annelot C M Van Esbroeck, Ross Mcguire, Herman S OverkleeftAbstract:sn-1-Diacylglycerol Lipase α (DAGL-α) is the main enzyme responsible for the production of the endocannabinoid 2-arachidonoylglycerol in the central nervous system. Glycine sulfonamides have recently been identified by a high throughput screening campaign as a novel class of inhibitors for this enzyme. Here, we report on the first structure–activity relationship study of glycine sulfonamide inhibitors and their brain membrane proteome-wide selectivity on serine hydrolases with activity-based protein profiling (ABPP). We found that (i) DAGL-α tolerates a variety of biaryl substituents, (ii) the sulfonamide is required for inducing a specific orientation of the 2,2-dimethylchroman substituent, and (iii) a carboxylic acid is essential for its activity. ABPP revealed that the sulfonamide glycine inhibitors have at least three off-targets, including α/β-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-α/ABHD6 inhibitor, which makes this compound a potential lead for the discove...
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Discovery of Glycine Sulfonamides as Dual Inhibitors of sn-1-Diacylglycerol Lipase α and α/β-Hydrolase Domain 6
Journal of Medicinal Chemistry, 2014Co-Authors: Freek J Janssen, Marc P Baggelaar, Hui Deng, Hans Den Dulk, Marco Allara, Alessia Ligresti, Annelot C M Van Esbroeck, Ross Mcguire, Vincenzo Di MarzoAbstract:sn-1-Diacylglycerol Lipase α (DAGL-α) is the main enzyme responsible for the production of the endocannabinoid 2-arachidonoylglycerol in the central nervous system. Glycine sulfonamides have recently been identified by a high throughput screening campaign as a novel class of inhibitors for this enzyme. Here, we report on the first structure–activity relationship study of glycine sulfonamide inhibitors and their brain membrane proteome-wide selectivity on serine hydrolases with activity-based protein profiling (ABPP). We found that (i) DAGL-α tolerates a variety of biaryl substituents, (ii) the sulfonamide is required for inducing a specific orientation of the 2,2-dimethylchroman substituent, and (iii) a carboxylic acid is essential for its activity. ABPP revealed that the sulfonamide glycine inhibitors have at least three off-targets, including α/β-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-α/ABHD6 inhibitor, which makes this compound a potential lead for the discove...
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acute inhibition of Diacylglycerol Lipase blocks endocannabinoid mediated retrograde signalling evidence for on demand biosynthesis of 2 arachidonoylglycerol
The Journal of Physiology, 2013Co-Authors: Yuki Hashimotodani, Asami Tanimura, Yoshihiro Kita, Takao Shimizu, Vincenzo Di Marzo, Takako Ohnoshosaku, Yoshikazu Sano, Masanobu KanoAbstract:Key points • 2-Arachidonoylglycerol (2-AG), one of the best-characterized retrograde messengers at central synapses, has been thought to be produced ‘on demand’ through a Diacylglycerol Lipase α (DGLα)-dependent pathway upon activation of postsynaptic neurons (on-demand synthesis hypothesis). • However, recent studies propose an alternative hypothesis that 2-AG is pre-synthesized by DGLα, stored in neurons, and released from such ‘pre-formed pools’ without the participation of DGLα (pre-formed pool hypothesis). • To test these hypotheses, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde 2-AG signalling. • We found that 2-AG-mediated retrograde signalling was blocked after 1 h treatment with OMDM-188 in acute slices from the hippocampus, striatum and cerebellum, and was blocked several minutes after OMDM-188 application in cultured hippocampal neurons. • These results fit well with the on-demand synthesis hypothesis, rather than the pre-formed pool hypothesis. Abstract The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) produced by Diacylglycerol Lipase α (DGLα) is one of the best-characterized retrograde messengers at central synapses. It has been thought that 2-AG is produced ‘on demand’ upon activation of postsynaptic neurons. However, recent studies propose that 2-AG is pre-synthesized by DGLα and stored in neurons, and that 2-AG is released from such ‘pre-formed pools’ without the participation of DGLα. To address whether the 2-AG source for retrograde signalling is the on-demand biosynthesis by DGLα or the mobilization from pre-formed pools, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde eCB signalling triggered by Ca2+ elevation, Gq/11 protein-coupled receptor activation or synergy of these two stimuli in postsynaptic neurons. We found that pretreatment for 1 h with OMDM-188 effectively blocked depolarization-induced suppression of inhibition (DSI), a purely Ca2+-dependent form of eCB signalling, in slices from the hippocampus, striatum and cerebellum. We also found that at parallel fibre–Purkinje cell synapses in the cerebellum OMDM-188 abolished synaptically induced retrograde eCB signalling, which is known to be caused by the synergy of postsynaptic Ca2+ elevation and group I metabotropic glutamate receptor (I-mGluR) activation. Moreover, brief OMDM-188 treatments for several minutes were sufficient to suppress both DSI and the I-mGluR-induced retrograde eCB signalling in cultured hippocampal neurons. These results are consistent with the hypothesis that 2-AG for synaptic retrograde signalling is supplied as a result of on-demand biosynthesis by DGLα rather than mobilization from presumptive pre-formed pools.
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endocannabinoids generated by ca2 or by metabotropic glutamate receptors appear to arise from different pools of Diacylglycerol Lipase
PLOS ONE, 2011Co-Authors: Longhua Zhang, Meina Wang, Tiziana Bisogno, Vincenzo Di Marzo, Bradley E AlgerAbstract:The identity and subcellular sources of endocannabinoids (eCBs) will shape their ability to affect synaptic transmission and, ultimately, behavior. Recent discoveries support the conclusion that 2-arachidonoyl glycerol, 2-AG, is the major signaling eCB, however, some important issues remain open. 2-AG can be synthesized by a mechanism that is strictly Ca2+-dependent, and another that is initiated by G-protein coupled receptors (GPCRs) and facilitated by Ca2+. An important question is whether or not the 2-AG in these cases is synthesized by the same pool of Diacylglycerol Lipase alpha (DAGLα). Using whole-cell voltage-clamp techniques in CA1 pyramidal cells in acute in vitro rat hippocampal slices, we investigated two mechanistically distinct eCB-mediated responses to address this issue. We now report that pharmacological inhibitors of DGLα have quantitatively different effects on eCB-mediated responses triggered by different stimuli, suggesting that functional, and perhaps physical, distinctions among pools of DAGLα exist.
Brian C Shonesy - One of the best experts on this subject based on the ideXlab platform.
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Cyclic AMP‐dependent protein kinase and D1 dopamine receptors regulate Diacylglycerol Lipase‐α and synaptic 2‐arachidonoyl glycerol signaling
Journal of Neurochemistry, 2020Co-Authors: Brian C Shonesy, Jason R Stephenson, Christian R Marks, Roger J ColbranAbstract:Brain endocannabinoids serve as retrograde neurotransmitters, being synthesized in post-synaptic neurons "on demand" and released to bind pre-synaptic cannabinoid receptors and suppress glutamatergic or GABAergic transmission. The most abundant brain endocannabinoid, 2 arachidonoyl glycerol (2-AG), is primarily synthesized by Diacylglycerol Lipase-alpha (DGLalpha), which is activated by poorly understood mechanisms in response to calcium influx following post-synaptic depolarization and/or the activation of Gq -coupled group 1 metabotropic glutamate receptors. However, the impact of other neurotransmitters and their downstream signaling pathways on synaptic 2-AG signaling has not been intensively studied. Here, we found that DGLalpha activity in membrane fractions from transfected HEK293T cells was significantly increased by in vitro phosphorylation using cyclic AMP-dependent protein kinase (PKA). Moreover, PKA directly phosphorylated DGLalpha at Ser798 in vitro. Elevation of cAMP levels in HEK293 cells expressing DGLalpha increased Ser798 phosphorylation, as detected using a phospho-Ser798-specific antibody, and enhanced DGLalpha activity; this in situ enhancement of DGLalpha activity was prevented by mutation of Ser798 to Ala. We investigated the impact of PKA on synaptic 2-AG mobilization in mouse striatal slices by manipulating D1-dopamine receptor (D1R) signaling and assessing depolarization-induced suppression of excitation, a DGLalpha- and 2-AG-dependent form of short-term synaptic depression. The magnitude of depolarization-enhanced suppression of excitation in direct pathway medium spiny neurons was increased by pre-incubation with a D1R agonist, and this enhancement was blocked by post-synaptic inhibition of PKA. Taken together, these findings provide new molecular insights into the complex mechanisms regulating synaptic endocannabinoid signaling.
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cyclic amp dependent protein kinase and d1 dopamine receptors regulate Diacylglycerol Lipase α and synaptic 2 arachidonoyl glycerol signaling
Journal of Neurochemistry, 2020Co-Authors: Brian C Shonesy, Jason R Stephenson, Christian R Marks, Roger J ColbranAbstract:: Brain endocannabinoids serve as retrograde neurotransmitters, being synthesized in post-synaptic neurons "on demand" and released to bind pre-synaptic cannabinoid receptors and suppress glutamatergic or GABAergic transmission. The most abundant brain endocannabinoid, 2 arachidonoyl glycerol (2-AG), is primarily synthesized by Diacylglycerol Lipase-α (DGLα), which is activated by poorly understood mechanisms in response to calcium influx following post-synaptic depolarization and/or the activation of Gq -coupled group 1 metabotropic glutamate receptors. However, the impact of other neurotransmitters and their downstream signaling pathways on synaptic 2-AG signaling has not been intensively studied. Here, we found that DGLα activity in membrane fractions from transfected HEK293T cells was significantly increased by in vitro phosphorylation using cyclic AMP-dependent protein kinase (PKA). Moreover, PKA directly phosphorylated DGLα at Ser798 in vitro. Elevation of cAMP levels in HEK293 cells expressing DGLα increased Ser798 phosphorylation, as detected using a phospho-Ser798-specific antibody, and enhanced DGLα activity; this in situ enhancement of DGLα activity was prevented by mutation of Ser798 to Ala. We investigated the impact of PKA on synaptic 2-AG mobilization in mouse striatal slices by manipulating D1-dopamine receptor (D1R) signaling and assessing depolarization-induced suppression of excitation, a DGLα- and 2-AG-dependent form of short-term synaptic depression. The magnitude of depolarization-enhanced suppression of excitation in direct pathway medium spiny neurons was increased by pre-incubation with a D1R agonist, and this enhancement was blocked by post-synaptic inhibition of PKA. Taken together, these findings provide new molecular insights into the complex mechanisms regulating synaptic endocannabinoid signaling.
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camkii regulates Diacylglycerol Lipase α and striatal endocannabinoid signaling
Nature Neuroscience, 2013Co-Authors: Brian C Shonesy, Xiaohan Wang, Kristie L Rose, Teniel S Ramikie, Victoria S Cavener, Tyler J Rentz, Anthony J Baucum, Nidhi Jalansakrikar, Ken Mackie, Danny G WinderAbstract:The endocannabinoid 2-AG is produced by the enzyme Diacylglycerol Lipase (DGL). The authors show that DGLα is phosphorylated and inhibited by calcium/calmodulin–dependent protein kinase II (CaMKII). Inhibition of CaMKII activity increases striatal DGL activity and basal 2-AG amounts, and augments short-term retrograde endocannabinoid signaling at striatal glutamatergic synapses.