Background:The ghrelin receptor (GHS-R1a) has multiple biological functionalities, including the regulation of appetite and hedonic food intake. Results: A novel GHS-R1a/5-HT 2C heterodimer was identified, in addition to GHS-R1a/D 1 and GHS-R1a/MC 3 . Conclusion: Promiscuous GHS-R1a receptor heterodimerization attenuates downstream signaling and affects trafficking depending on dimer partner. Significance: The existence of multiple GHS-R1a heterodimers has important consequences for the future development of therapeutics with enhanced specificity.
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
The ghrelin receptor [growth hormone secretagogue receptor (GHSR)‐1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR‐1a has a complex pharmacology, highlighted by G‐protein–dependent and—independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR‐1a–specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK‐0677, L692,585, and [d‐Lys3]‐growth hormone–releasing peptide‐6 (Dlys), JMV2959, and [d‐Arg(1),d‐Phe(5),d‐Trp(7, 9), Leu(11)]‐substance P (SP‐analog). We investigated their effect on basal GHSR‐1a constitutive signaling, ligand‐directed downstream GHSR‐1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR‐1a–β‐arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR‐1a antagonist. Moreover, the SP‐analog behaved as an inverse agonist increasing G‐protein–dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP‐analog attenuated β‐arrestin–dependent signaling. Considering the limited success in the clinical development of GHSR‐1a–targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR‐1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR‐1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.—Ramirez, V. T., van Oeffelen, W. E. P. A., Torres‐Fuentes, C., Chruścicka, B., Druelle, C., Golubeva, A. V., van de Wouw, M., Dinan, T. G., Cryan, J. F., Schellekens, H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. FASEB J. 33, 518–531 (2019). http://www.fasebj.org
22This study investigates the ability of milk protein-derived peptides to specifically activate the 23 serotonin 2C (5-HT 2C ) receptor, a key receptor in central regulation of food intake. A dose 24 dependent 5-HT 2C receptor activation by the 1 kDa ultrafiltration permeates of a sodium 25 caseinate (NaCNH-1 kDa permeate) and a whey protein hydrolysate (WPH-1 kDa permeate) 26 was demonstrated using an intracellular calcium mobilization assay in human embryonic 27 kidney (Hek) cells expressing the 5-HT 2C receptor. Both samples activated the 5-HT 2C but not 28 the 5-HT 2A and 5-HT 2B receptors. NaCNH-1 kDa permeate significantly (p < 0.01) reduced 29 cumulative food intake when administered to male mice (C57Bl/6) by intraperitoneal 30 injection at 500 mg kg -1 body weight. In contrast, no effect of WPH-1 kDa permeate could be 31 seen on food intake in vivo. These results demonstrate the promising appetite-suppressing 32 potential of NaCN-derived peptides, targeting the 5-HT 2C receptor. 33
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