Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

Callén, Lucía; Moreno, Elsa Moreno; Barroso‐Chinea, Pedro; Moreno‐Delgado, David; Cortés, Antoni; Mallol, Josefa; Casadó, Vicent; Lanciego, José L.; Franco, Rafael; Lluı́s, Carmen; Canela, Enric I.; McCormick, Peter J.

doi:10.1074/jbc.m111.335273

Cited by 207 publications

(152 citation statements)

References 90 publications

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“…More recently, coimmunoprecipitation assays in HEK293 cells have suggested that CB 1 R can form heteromers with GPR55 (32). In contrast to CB 1 R, very little is known about the possible existence and functional relevance of heteromers involving CB 2 R. A recent study has shown that CB 2 R heteromerizes with CB 1 R in neuronal cells in culture and in vivo (19). In these systems, coactivation of both receptors results in a negative cross-talk and a bidirectional cross-antagonism (19).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to CB 1 R, very little is known about the possible existence and functional relevance of heteromers involving CB 2 R. A recent study has shown that CB 2 R heteromerizes with CB 1 R in neuronal cells in culture and in vivo (19). In these systems, coactivation of both receptors results in a negative cross-talk and a bidirectional cross-antagonism (19). However, CB 2 R signaling can be conceivably more relevant in non-differentiated cells, in which the receptor is highly abundant, than in terminally differentiated cells such as neurons, in which the receptor is scarce (3,33).…”

Section: Discussionmentioning

confidence: 99%

“…The amplified fragments were subcloned to be in-frame with Renilla luciferase (Rluc) into the EcoRI and BamHI restriction sites of the pcDNA3.1-RLuc vector (pRLuc-N1, PerkinElmer Life Sciences) or the pEYFP-N1 vector (enhanced yellow variant of GFP, Clontech, Heidelberg, Germany) to generate the plasmids that express proteins fused to RLuc or YFP on the C-terminal end (GPR55-RLuc, CB 2 R-YFP, and Ghrelin 1a receptor-YFP). The expression of the constructs was tested as described previously (19). HEK293 or BT474 cells were transiently cotransfected with a constant amount of cDNA encoding for proteins fused to Rluc as a BRET donor and with increasing amounts of the cDNA corresponding to proteins fused to YFP as a BRET acceptor.…”

Section: Methodsmentioning

confidence: 99%

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Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

Moreno

Andradas

Medrano

et al. 2014

Journal of Biological Chemistry

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102

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Background: Cannabinoid receptor CB 2 (CB 2 R) and GPR55 are overexpressed in cancer cells and control cell fate. Results: In cancer cells, CB 2 R and GPR55 form heteromers that impact the signaling of each protomer. Conclusion: CB 2 R-GPR55 heteromers drive biphasic signaling responses as opposed to the individual receptors via cross-antagonism. Significance: These heteromers may explain some of the biphasic effects of cannabinoids and, therefore, constitute potential new targets in oncology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

Moreno

Andradas

Medrano

et al. 2014

Journal of Biological Chemistry

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102

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“…Indeed, there is controversy regarding the effects of endocannabinoids and congeners at GRP55, due to the different results obtained with different functional assays in various biological systems (786). It is possible that different biased signaling properties of these ligands, and tissue and celldependent coupling of GPR55 with different G proteins and effector systems, or with CB1 or CB2 in heteromers, all contribute to this heterogeneity of results (110,537,592).…”

Section: B Other Receptors For Endocannabinoidsmentioning

confidence: 99%

“…In particular, CB1 receptors were shown to form homodimers by using a "dimer antibody" as well as classical immunoprecipitation techniques, and were also reported to make heterodimers with D2 dopamine, A 2a adenosine, OX-1 orexin, 5-HT 2a serotonin, opioid, AT1 angiotensin II, and GPR55 receptors, the latter of which form heterodimers also with CB2 receptors (373, 509, 592, 669). Interestingly, there is also a report of the occurrence in the brain of CB1/CB2 heterodimers, the coactivation of which results in a negative crosstalk over Akt phosphorylation and neurite outgrowth (110).…”

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confidence: 99%

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

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

377

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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Endocannabinoid System: An Update

Battista

Maccarrone

Bari

2017

Encyclopedia of Life Sciences

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The endocannabinoid system (ECS) is nowadays considered as an important neurotransmitter system and, although the chemistry, biochemistry and pharmacology of endocannabinoids (eCBs) have been widely investigated, quite some pieces are still missing to fully understand how this system works. The discovery of anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) dates back to the beginning of 1990 and, since then, their molecular targets, biosynthetic and catabolic enzymes have been identified. In addition, selective pharmacological and genetic tools have been developed both to explore alternative metabolic routes and to produce eCB‐based drugs as therapeutics for the prevention/treatment of a variety of diseases. In this article, we will review the metabolic pathways of eCBs, and the latest advances on their potential receptor targets. Key Concepts The endocannabinoid system is an endogenous network including endocannabinoids, a complex array of receptors, biosynthetic and hydrolytic enzymes, as well as membrane transporters. Endocannabinoids are derivatives of the arachidonic acid. The two most important endocannabinoid transmitters, anandamide and 2‐arachidonoylglycerol, are produced and eliminated through several enzyme pathways. Endocannabinoids play their main roles by targeting both cannabinoid and other membrane and nuclear receptors. The binding of endocannabinoids to cannabinoid, vanilloid and peroxisome proliferator‐activated receptors triggers several signal transduction pathways. The endocannabinoid system is a pleiotropic signalling system that is widely distributed in the central and peripheral nervous systems. Alterations of circulating endocannabinoids levels are involved in the dysregulation of activity of important physiological systems. A deep knowledge of the endocannabinoid system signalling might be translated into the development of pathway‐selective drugs for therapeutic benefit.

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Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

Cited by 207 publications

References 90 publications

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

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

Endocannabinoid System: An Update

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