Identification of intracellular carriers for the endocannabinoid anandamide

Kaczocha, Martin; Glaser, Sherrye T.; Deutsch, Dale G.

doi:10.1073/pnas.0901515106

Cited by 308 publications

(354 citation statements)

References 64 publications

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“…The decreased responsiveness to OEA in L-Fabp Ϫ / Ϫ mice may also refl ect alterations in intracellular traffi cking. Recent studies showed that overexpression of FABP7 and FABP5 increased uptake and hydrolysis of AEA in Cos7 cells, suggesting that FABPs may facilitate the intracellular traffi cking of this hydrophobic ligand ( 13 ). It is tempting to speculate that L-Fabp may play a role in facilitating intracellular movement of either fatty acids for FAE synthesis Supplemental Material can be found at:…”

Section: Discussionmentioning

confidence: 99%

“…1A ) after 5 months of age, with decreased fat mass as determined by both MRI ( Fig. 1B ) and DEXA (data not shown) analysis at carrier proteins, including fatty acid binding proteins (FABP), in the metabolic compartmentalization of these mediators ( 13,14 ). L-Fabp is an abundant cytosolic FABP expressed in hepatocytes and in enterocytes of the proximal small intestine.…”

Section: Aged Female L-fabpmentioning

confidence: 99%

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Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Newberry

Kennedy

Luo

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org dramatically in the past 20 years, in parallel with the epidemic of obesity. Although environmental factors (caloric excess) and lifestyle choices (lack of exercise) are the primary causes, genetic susceptibility also predisposes individuals to obesity and its metabolic complications. Studies have identifi ed mechanisms by which food consumption is regulated, including release of factors produced within the gastrointestinal tract (CCK, ghrelin, PYY, lipid amides, and palmitoleic acid) that mediate satiety either locally or centrally ( 1 ).Recent studies have identifi ed several lipid messengers that regulate feeding behavior ( 2-5 ). These include the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (endogenous ligands of the cannabinoid receptors); the fatty acid ethanolamides (FAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA); and their biosynthetic precursors, the N -acyl-phosphatidylethanolamines ( 6, 7 ). OEA is an ubiquitous lipid molecule that is synthesized in the proximal small intestine following consumption of dietary fat, and it promotes satiety by binding nuclear peroxisome proliferator-activated receptor-␣ (PPAR ␣ ) and activating vagal efferents ( 8-10 ). Conversely, AEA promotes food consumption through activation of CB 1 cannabinoid receptors both in the brain and peripheral tissues. In addition, AEA regulates systemic energy utilization, infl ammation, apoptosis, and pain ( 11, 12 ). Details of how the balance between opposing satiety and orexigenic factors is maintained are a focus of investigation, but there is increasing evidence for a role of intracellular The prevalence of nonalcoholic fatty liver disease, type II diabetes, and the metabolic syndrome has increased

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Section: Discussionmentioning

confidence: 99%

Section: Aged Female L-fabpmentioning

confidence: 99%

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Newberry

Kennedy

Luo

et al. 2012

Journal of Lipid Research

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“…Considering the fact that AEA does not bind appreciably to borosilicate glass, the use of coverslips seems particularly indicated to perform export experiments. More importantly, the new procedure can be also extended to the subcellular level ( 49,50 ) by taking advantage of b-AEA as a nonradioactive probe to look at anandamide traffi cking within intact cells by light, fl uorescence, and electron microscopy techniques.…”

Section: Discussionmentioning

confidence: 99%

Pitfalls and solutions in assaying anandamide transport in cells

Oddi¹,

Fezza²,

Catanzaro³

et al. 2010

Journal of Lipid Research

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functions, both in the central nervous system and in the periphery, by binding to type-1 and type-2 cannabinoid receptors ( 1 ), and to transient receptor potential vanilloid 1 (TRPV1) ion channels ( 2, 3 ). Additional targets of AEA also include 5-hydroxytryptamine receptors ( 4 ), GPR55 or "CB3R" ( 5, 6 ), and the nuclear peroxisome proliferatoractivated receptors ␣ ( 7, 8 ) and ␥ ( 9-11 ).AEA is thought to act as an autocrine/paracrine mediator by activating these receptors either on the cell surface (cannabinoid receptors) or within the cell (TRPV1 and peroxisome proliferator-activated receptors). Extracellular AEA signaling is terminated through a two-step process consisting of transport inside the cell and subsequent hydrolysis by fatty acid amide hydrolase (FAAH) ( 12 ). The process whereby AEA is transported across the plasma membrane and within the cell is considered a hot topic, because it is a potential target for treatment of several pathologies associated with endocannabinoid system dysfunctions ( 13-21 ).Despite considerable experimental efforts made to clarify the mechanism of AEA transport, there is not yet general consensus on the identity of the elements responsible for this process [see ( 22 ) for a very recent review]. In general, fi ve nonmutually exclusive models have been proposed: i ) passive diffusion ( 23,24 ); ii ) facilitated transport ( 25-27 ); iii ) intracellular traffi cking and sequestration ( 24, 27, 28 ); iv ) endocytosis ( 29, 30 ); and v ) FAAH-mediated uptake ( 31-33 ). These mechanisms might also operAbstract Nonspecifi c binding of anandamide to plastic exhibits many features that could be mistaken as biological processes, thereby representing an important source of confl icting data on the uptake and release of this lipophilic substance. Herein, we propose an improved method to assay anandamide transport, by using glass slides (i.e., coverslips) as physical support to grow cells. Although the results obtained using plastic do not differ signifi cantly from those obtained using glass, the new procedure has the advantage of being faster, simpler, and more accurate. In fact, the lack of aspecifi c adsorption of anandamide to the glass surface yields a lower background and a higher precision and accuracy in determining transport kinetics, especially for the export process. Remarkably, the kinetic parameters of anandamide uptake obtained with the old and the new procedures may be similar or different depending on the cell type, thus demonstrating the complexity of the interference of plastic on the transport process. In addition, the novel procedure is particularly suitable for visualization and measurement of anandamide transport in intact cells by using a biotinylated derivative in confocal fl uorescence microscopy.

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“…Although this model supports the existence of a plasma membrane-localized AEAbinding protein, it cannot explain why uptake inhibitors also affect AEA efflux. Right after the identification of several cytosolic AEA "chaperone" proteins, such as FABP5, FABP7, Hsp70, albumin, and the more controversial FLAT (274,415,637,773), a revised version of the simple diffusion model was proposed. According to this model, the passive diffusion process of AEA across the membrane is followed by intracellulaer carrier-mediated transport to effector proteins, catabolic enzymes, and sequestration sites (268,270).…”

Section: Endocannabinoid Biosynthesis and Degradationmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

363

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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Identification of intracellular carriers for the endocannabinoid anandamide

Cited by 308 publications

References 64 publications

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Pitfalls and solutions in assaying anandamide transport in cells

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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