A catalytically silent FAAH-1 variant drives anandamide transport in neurons

Fu, Jin; Bottegoni, Giovanni; Sasso, Oscar; Bertorelli, Rosalia; Rocchia, Walter; Masetti, Matteo; Guijarro, Ana; Lodola, Alessio; Armirotti, Andrea; Garau, Gianpiero; Bandiera, Tiziano; Reggiani, Angelo; Mor, Marco; Cavalli, Andrea; Piomelli, Daniele

doi:10.1038/nn.2986

Cited by 153 publications

(146 citation statements)

References 48 publications

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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

365

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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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

365

337

View full text Add to dashboard Cite

show abstract

“…(4) FLAT was reported as a critical molecular component of anandamide transport in neural cells [44]. The study showed that FLAT is a catalytically silent splice variant of FAAH, is expressed robustly throughout the brain, and facilitates the translocation of anandamide into cells.…”

Section: Other Possible Mechanismsmentioning

confidence: 99%

Endocannabinoid-mediated retrograde modulation of synaptic transmission

Ohno‐Shosaku

Kano

2014

Current Opinion in Neurobiology

198

141

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One of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), serves as a retrograde messenger at various types of synapses throughout the brain. Upon postsynaptic activation, 2-AG is released immediately after de novo synthesis, activates presynaptic CB 1 cannabinoid receptors, and transiently suppresses neurotransmitter release. When CB 1 receptor activation is combined with some other factors such as presynaptic activity, the suppression is converted to a long-lasting form. Whereas 2-AG primarily transmits a rapid, transient, point-to-point retrograde signal, the other major endocannabinoid, anandamide, may function as a relatively slow retrograde or non-retrograde signal or as an agonist of the vanilloid receptor. The endocannabinoid system can be up-or down-regulated by a variety of physiological and environmental factors including stress, which might be clinically important.

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“…Moving to the inhibition of endocannabinoid cellular uptake, there are some potential therapeutic effects observed with the use of membrane transporter inhibitors in animal models (30,38,40). This approach has once again gained attention after the recent discovery of FAAH-like anandamide transporter (49), but clinical research remains to be determined.…”

Section: Modulation Of the Endocannabinoid Systemmentioning

confidence: 99%

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Ulugöl¹

2014

Balkan Med J

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Cannabinoids are a group of chemical compounds that produce their effects via activating cannabinoid receptors; they include the phytocannabinoids (herbal cannabinoids/natural cannabinoids found in the cannabis plant), synthetic cannabinoids, and endogenous cannabinoids (endocannabinoids) (1, 2). Cannabis, also known as marijuana, has been used as both a recreational and medicinal drug for centuries. Pain management is the most important among the medicinal purposes, and has been drawing intense attention following the discovery of cannabinoid receptors and their endogenous ligands, endocannabinoids (3-5). ∆ 9 -tetrahydrocannabinol (THC) and cannabidiol, the critical components of the cannabis plant, and the synthetic cannabinoids and their analogues have been shown to exert strong analgesic action both in preclinical and clinical studies (6)(7)(8)(9). In this review, after a brief introduction to cannabinoid receptors, phytocannabinoids and synthetic cannabinoids, I provide an overview of what is currently known about the synthesis, release, degradation and biological actions of endocannabinoids, regarding their role in pain modulation, and describe the recent evidence of the promising results of augmentation of endogenous cannabinoid tonus for the treatment of pain. CANNABINOID RECEPTORS AND THE SITE OF ACTION OF CANNABINOIDSTo date, two subtypes of cannabinoid receptors, termed cannabinoid-1 (CB 1 ) and cannabinoid-2 (CB 2 ) receptors, have been cloned (10, 11). CB 1 receptors are most abundantly expressed in the central nervous system (CNS), most densely in motor and limbic regions, and in areas that are involved in pain transmission and modulation, such as periaqueductal grey (PAG), rostral ventromedial medulla (RVM), spinal cord dorsal horn, and in the periphery. CB 1 receptors are generally located pre-synaptically on axons and terminals of neurons and mediate the inhibition of neurotransmitter release by the inhibition of adenylate cyclase, blockade of voltage-dependent calcium channels, and/or by the activation of potassium channels and mitogen-activated protein kinase. CB 2 receptors, on the other hand, are found mainly, but not exclusively, outside the CNS, predominantly in peripheral tissues with immune functions, and most densely in the spleen. Similar to CB 1 receptors, CB 2 receptors are also G-protein coupled, inhibits adenylate cyclase and produce cellular inhibition, but neither blockade of calcium channels Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targe...

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A catalytically silent FAAH-1 variant drives anandamide transport in neurons

Cited by 153 publications

References 48 publications

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

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

Endocannabinoid-mediated retrograde modulation of synaptic transmission

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

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