Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Ward, Richard J.; Pediani, John D.; Milligan, Graeme

doi:10.1074/jbc.m111.287649

Cited by 81 publications

(77 citation statements)

References 68 publications

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“…Indeed, such receptor variants (i.e. SNAP and CLIP-tagged receptors) have been utilized in the studying of CB 1 R internalization (Ward et al, 2011a(Ward et al, , 2011b). Here we used another variant, the HaloTag labeled form of CB 1 R. As indicated in our study, G protein activation and β-arrestin binding of Halo-CB 1 R have not been altered due to the N-terminal labeling, and therefore this receptor can be used to study receptor trafficking with the same advantages as the above mentioned ones.…”

Section: Discussionmentioning

confidence: 99%

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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CB 1 cannabinoid receptor (CB 1 R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB 1 R function are not completely understood. In this study, we followed CB 1 R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB 1 R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB 1 R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB 1 R. However, both constitutive and agonist-induced internalization of CB 1 R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB 1 R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB 1 R are different.

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Section: Discussionmentioning

confidence: 99%

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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“…In agreement with a functional interaction between hypocretins and cannabinoids in reward-related processes, it has been recently shown that the intra-VTA administration of the CB 1 cannabinoid antagonist AM251 blocks the conditioned place preference induced by the chemical stimulation of LH hypocretin neurons (47). Moreover, hcrtr-1 and CB 1 cannabinoid receptors form heterodimers (48) suggesting the existence of a cross-talk between these two systems which will require future investigation.…”

Section: The Enhanced Of Dopamine Extracellular Levels In the Nucleusmentioning

confidence: 91%

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

Flores

Maldonado

Berrendero

2014

Biological Psychiatry

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Table 1) 2 Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacological treatment is still available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction and the potential participation of this system in the addictive properties of cannabinoids is still unknown. Methods:We investigated the effects of hypocretins in the intravenous selfadministration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 (Hcrtr-2) antagonists, and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double label immunofluorescence of FosB/∆FosB with hypocretin-1.Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute ∆ 9 -tetrahydrocannabinol (THC) administration.Results: Systemic administration of the Hcrtr-1 antagonist SB334867, but not the Hctr-2 antagonist TCSOX229, reduced intravenous self-administration of WIN55,212-2 as well as the maximum effort to obtain a WIN55,212-2 infusion as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not non-contingent WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/∆FosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by THC was blocked in mice lacking the Hcrtr-1.Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest. 3 IntroductionCannabis is the most used illicit drug worldwide (1). It is estimated that about 9% of those who ever use this drug become daily users (2), rising to 16% when the consumption is initiated during the adolescence (2). Recent analysis of cannabis extracts has shown an increase in potency over the last years due to enhanced content of ∆ 9 -tetrahydrocannabinol (THC), its primary psychoactive constituent (3). A high THC content leads to an increase in the subjective effects of this drug probably enhancing the risk of dependence and psychotic symptoms of cannabis users (3). Treatment admissions for cannabis-use disorders have progressively increased in the past decade.Approximately 90% of those seeking treatment for these disorders have great difficulty achieving and sustaining periods of abstinence (4), and the majority relapse to use following therapeutic interventions (5). There are currently no effective pharmacotherapeutic approaches for this disorder (5). Therefore, the need for identifying specific medications to improve treatment outcomes for cannabis dependence becomes a major clinical priority.Several findin...

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“…25 In an in vitro study, it was demonstrated that the coexpression of CB1 and OX1 receptors results in a higher potentiation of ERK signalling, possibly because of heterodimerization/oligomerization of these two receptors. 26 Recently, however, it was also shown that 2-AG produced and released through the activation of OX1 receptor acts as both a paracrine and autocrine messenger via CB1 receptors, 23,27 thus possibly explaining the above-mentioned findings in the rat dorsal raphe nucleus and periaqueductal gray, as well as the potentiation of ERK phoshorylation that follows OX1/CB1 receptor coexpression. These data suggest the involvement of 2-AG and CB1 receptors not only in orexin-A release but also in orexin-mediated regulation of synaptic transmission.…”

Section: Leptin-mediated Hypothalamic Ecb/orexin Interactionsmentioning

confidence: 98%

New horizons on the role of cannabinoid CB1 receptors in palatable food intake, obesity and related dysmetabolism

2014

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Excessive consumption of high-energy, palatable food contributes to obesity, which results in the metabolic syndrome, heart disease, type-2 diabetes and death. Current knowledge on the function of the hypothalamus as the brain 'feeding centre' recognizes this region as the main regulator of body weight in the central nervous system. Because of their intrinsically fast and adaptive activities, feeding-controlling neural circuitries are endowed with synaptic plasticity modulated by neurotransmitters and hormones that act at different hierarchical levels of integration. In the hypothalamus, among the chemical mediators involved in this integration, endocannabinoids (eCBs) are ideal candidates for the fast (that is, nongenomic), stress-related fine-tuning of neuronal functions. In this article, we overview the role of the eCB system (ECS) in the control of energy intake, and particularly in the consumption of high-energy, palatable food, and discuss how such a role is affected in the brain by changes in the levels of feeding-regulated hormones, such as the adipose tissue-derived anorexigenic mediator leptin, as well as by high-fat diets. The understanding of the molecular mechanisms underlying the neuronal control of feeding behaviours by eCBs offers many potential opportunities for novel therapeutic approaches against obesity. Highlights of the latest advances in the development of strategies that minimize central ECS overactivity in 'western diet'-driven obesity are discussed.International Journal of Obesity Supplements (2014) 4, S26--S30; doi:10.1038/ijosup.2014.8Keywords: CB1; hypothalamus; leptin; high-fat diet; synaptic rewiring; endocannabinoids INTRODUCTIONThe hypothalamus is the most extensively interconnected area of the brain, and through its wide web of neural circuits it controls a variety of essential autonomic and somatomotor functions. Neuroanatomical studies have demonstrated direct projections to hypothalamic areas from several brain regions such as cortical/ limbic areas and autonomic motor systems of the brainstem. Such extensive connectivity is thought to represent the anatomical basis supporting sleep--wake regulation, energy homeostasis and cognitive and reward-related functions.1 Hormonal and nutrient signals are processed in the hypothalamus and inform the brain about the free and stored levels of fuel available to the organism. In turn, the hypothalamic neuronal circuits use this information to regulate energy intake, energy expenditure and peripheral lipid and glucose metabolism.2 Because of their intrinsic functional activities, and the necessity to adapt to often significant changes in nutritional status, neural feeding circuitries are endowed with synaptic plasticity modulated by neurotransmitters and hormones that act at different hierarchical levels of integration.1 Among the chemical mediators involved in this integration, the endocannabinoids (eCBs) are the master regulators of the fast (that is, nongenomic) and stress-related fine-tuning of energy intake and processing. The eCB sys...

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Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Cited by 81 publications

References 68 publications

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

New horizons on the role of cannabinoid CB1 receptors in palatable food intake, obesity and related dysmetabolism

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