Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling

Schellekens, Harriët; Oeffelen, Wesley E. P. A. van; Dinan, Timothy G.; Cryan, John F.

doi:10.1074/jbc.m112.382473

Cited by 126 publications

(174 citation statements)

References 70 publications

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“…Recently, a novel heterodimer between the ghrelin receptor (GHS-R1A) and the unedited 5-HT2C receptor has been identified. Dimerization of GHS-R1A receptor with the unedited 5-HT2C receptor reduced the GHS-1RA receptor-mediated calcium influx [199].…”

Section: Brain Mechanisms Of Serotonergic Satietymentioning

confidence: 93%

“…Another approach to 5-HT2C receptor pharmacology in the context of obesity could arise from the dimerization of this G-protein coupled receptor as demonstrated with the ghrelin receptor [199,354]. Although this concept of warrants further research, dimerization of the 5-HT2C receptor increases the pharmacological diversity of this receptor and thus the development of new drugs.…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

“…If such an intracellular "protein serotonylation" [383,384] is involved in brain mechanisms of satiety remains to be investigated though. Together with the aforementioned approach to make pharmacological use of receptor dimerization [199], one could expect an increasingly diverse approach to interact with 5-HT2C receptors to tackle obesity.…”

Section: Serotonin and Satiety -What Is Next?mentioning

confidence: 99%

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Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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Section: Brain Mechanisms Of Serotonergic Satietymentioning

confidence: 93%

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Section: Serotonin and Satiety -What Is Next?mentioning

confidence: 99%

See 1 more Smart Citation

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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“…This is in line with our previous study and confirms the 5-HT2C receptor-mediated attenuation of GHS-R1a receptor signalling, which concurs the interaction between the two receptors 27 . Previously, it has been shown that the GHS-R1a receptor dimerizes with the dopamine D1 receptor leading to an enhanced dopamine induced c-AMP accumulation 24 and an attenuation of GHS-R1a-mediated calcium signalling 27 . This may suggest a dimer-induced switch in GHS-R1a receptor G-protein coupling from Gαq to Gαs, which has been previously suggested for neuronal GHS-R1a receptors expressed in neuropeptide Y (NPY) cells of the arcuate nucleus of the hypothalamus 69 .…”

Section: Resultsmentioning

confidence: 99%

“…However, recently, the GHS-R1a receptor has also been shown to heterodimerize with other GPCRs involved in appetite regulation and food reward (for review see 19 ), including its truncated splice variant, the GHS-R1b receptor 18,[20][21][22] , the melanocortin 3 receptor (MC3) and the dopamine receptors (D1 and D2) [23][24][25][26][27] . Moreover, our lab has demonstrated compelling evidence for a functional interaction between the GHS-R1a and the 5-HT2C receptor 27 .…”

Section: Introductionmentioning

confidence: 99%

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Schellekens¹,

Francesco²,

Kandil³

et al. 2015

ACS Chem. Neurosci.

Self Cite

107

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Understanding the intricate pathways modulating appetite and subsequent food intake is of particular importance considering the rise in obesity incidence across the globe. The serotonergic system, specifically the 5-HT2C receptor, has shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor wellknown for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signalling is not due to coupling to GαS, as no increase in cAMP signalling is observed. Next, flowcytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor.In addition, we demonstrate co-localized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic-and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signalling is blocked, ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into biological significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management. ACS Paragon Plus Environment ACS Chemical Neuroscience 5

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C/D‐box snoRNAs form methylating and non‐methylating ribonucleoprotein complexes: Old dogs show new tricks

et al. 2017

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C/D box snoRNAs (SNORDs) are an abundantly expressed class of short, non-coding RNAs that have been long known to perform 2′-O-methylation of rRNAs. However, approximately half of human SNORDs have no predictable rRNA targets, and numerous SNORDs have been associated with diseases that show no defects in rRNAs, among them Prader-Willi syndrome, Duplication 15q syndrome and cancer. This apparent discrepancy has been addressed by recent studies showing that SNORDs can act to regulate pre-mRNA alternative splicing, mRNA abundance, activate enzymes, and be processed into shorter ncRNAs resembling miRNAs and piRNAs. Furthermore, recent biochemical studies have shown that a given SNORD can form both methylating and non-methylating ribonucleoprotein complexes, providing an indication of the likely physical basis for such diverse new functions. Thus, SNORDs are more structurally and functionally diverse than previously thought, and their role in gene expression is under-appreciated. The action of SNORDs in non-methylating complexes can be substituted with oligonucleotides, allowing devising therapies for diseases like Prader-Willi syndrome.

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Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling

Cited by 126 publications

References 70 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

C/D‐box snoRNAs form methylating and non‐methylating ribonucleoprotein complexes: Old dogs show new tricks

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