Apo-Ghrelin Receptor Forms Heteromers with DRD2 in Hypothalamic Neurons and Is Essential for Anorexigenic Effects of DRD2 Agonism

Kern, András; Albarran-Zeckler, Rosie; Walsh, Heidi E.; Smith, Roy G.

doi:10.1016/j.neuron.2011.10.038

Cited by 282 publications

(334 citation statements)

References 53 publications

Supporting

Mentioning

304

Contrasting

Unclassified

Order By: Relevance

“…1C). Molecule size cutoff was below 70 kDa, with a step-like decrease in permeability rate between 20 and 40 kDa ( To investigate the transfer rate of ghrelin (3.3 kDa), a recently developed bioactive fluorescently labeled ghrelin derivative (3.8 kDa), capable of specifically binding and activating growth hormone secretagogue receptor-1a (GHS-R-1a) (19,20), was used. The extravasation rate of fluorescent ghrelin across the ME capillary barrier was comparable to that of 4-kDa FITC-conjugated dextran (∼0.8 μm/s) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

268

198

View full text Add to dashboard Cite

To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood-brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.hormone diffusion | in vivo imaging | median eminence | metabolism C ontinuous integration of peripheral signals by neurons belonging to the arcuate nucleus of the hypothalamus (ARH) is critical for central regulation of energy balance and neuroendocrine function (1). To dynamically report alterations to homeostasis and ensure an appropriate neuronal response, blood-borne factors such as hormones must rapidly access the central nervous system (CNS). This is particularly evident in the case of food intake, which is regulated by a plethora of circulating satiety signals (2) whose levels fluctuate in an ultradian manner. Despite this, it remains unclear how key energy status-signaling hormones such as ghrelin can be rapidly sensed by target neurons to alter feeding responses (3). Elucidation of the mechanisms underlying molecule entry into the brain is important for understanding not only normal maintenance of homeostasis but also how this is perturbed during common pathologies such as obesity and diabetes (4, 5).Although molecule transport mechanisms within the ARH are poorly characterized, they likely assume one of two forms. First, chronic feedback may be accomplished by uptake of circulating molecules into the ARH via saturable receptor-mediated transport at the level of the choroid plexus and/or bloodbrain barrier (BBB) (6-9). Second, the ARH is morphologically located in close apposition to the median eminence (ME), a circumventricular organ composed of fenestrated capillaries. Because these vessels project toward the ventromedial ARH (vmARH), they could represent a direct vascular input for passive diffusion of peripheral molecules into the hypothalamus (10-13). So far, study of the functional importance of fenestrated capillaries in molecule entry into the metabolic brain has been impeded by lack of appropriate tools.To evaluate the role of fenestrated ME/ARH capillaries in rapid detection of peripheral signals by the hypothalamus, we used a recently developed in vivo imaging approach to visualize in real time the extravasation of fluorescent molecules (14). Ghrelin was chosen as a candidate hormone because i...

show abstract

Section: Resultsmentioning

confidence: 99%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

268

198

View full text Add to dashboard Cite

show abstract

“…Further support for a role of GHS‐R1A in reward regulation is the human genetic data showing that a single nucleotide polymorphism in the GHS‐R1A gene is associated with high alcohol consumption in humans (Landgren et al., 2008). Given that GHS‐R1A has been shown to alter the sensitivity of the mesolimbic dopamine system via its ability to heterodimerize with dopamine D1‐ and D2‐like receptors (Jiang et al., 2006; Kern et al., 2012) as well as via its constitutive activity (Holst et al., 2003), we hypothesize that ventral tegmental GHS‐R1A are important for reward processes and for development of alcohol use disorder. Given that ghrelin is an orexigenic peptide and that alcohol contains calories, it should be considered that the ability of GHS‐R1A antagonists to reduce alcohol intake is due to interference with alcohol's calorific value and rather than its rewarding properties.…”

Section: Discussionmentioning

confidence: 99%

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

Jerlhag

Ivanoff

Vater

et al. 2014

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

BackgroundDevelopment of alcohol dependence, a chronic and relapsing disease, largely depends on the effects of alcohol on the brain reward systems. By elucidating the mechanisms involved in alcohol use disorder, novel treatment strategies may be developed. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor 1A, acts as an important regulator of energy balance. Recently ghrelin and its receptor were shown to mediate alcohol reward and to control alcohol consumption in rodents. However, the role of central versus peripheral ghrelin for alcohol reward needs to be elucidated.MethodsGiven that ghrelin mainly is produced by peripheral organs, the present study was designed to investigate the role of circulating endogenous ghelin for alcohol reward and for alcohol intake in rodents.ResultsWe showed that the Spiegelmer NOX‐B11‐2, which binds and neutralizes acylated ghrelin in the periphery with high affinity and thus prevents its brain access, does not attenuate the alcohol‐induced locomotor activity, accumbal dopamine release and expression of conditioned place preference in mice. Moreover, NOX‐B11‐2 does not affect alcohol intake using the intermittent access 20% alcohol 2‐bottle‐choice drinking paradigm in rats, suggesting that circulating ghrelin does not regulate alcohol intake or the rewarding properties of alcohol. In the present study, we showed however, that NOX‐B11‐2 reduced food intake in rats supporting a role for circulating ghrelin as physiological regulators of food intake. Moreover, NOX‐B11‐2 did not affect the blood alcohol concentration in mice.ConclusionsCollectively, the past and present studies suggest that central, rather than peripheral, ghrelin signaling may be a potential target for pharmacological treatment of alcohol dependence.

show abstract

“…This aspect is presently the subject of intense research (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for recent reviews). In recent years, such an effort allowed the characterization of a panel of receptor complexes representing possible targets for the treatment of pathologic conditions, such as Parkinson's disease , schizophrenia and depression Sahlholm et al, 2017), neuropathic pain , addiction (Gomes et al, 2013), and food intake disorders (Kern et al, 2012). On this basis, novel strategies for drug treatment have also been proposed.…”

Section: Introductionmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

View full text Add to dashboard Cite

Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

show abstract

Apo-Ghrelin Receptor Forms Heteromers with DRD2 in Hypothalamic Neurons and Is Essential for Anorexigenic Effects of DRD2 Agonism

Cited by 282 publications

References 53 publications

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Contact Info

Product

Resources

About