Growth Hormone Secretagogue Receptor (GHSR1a, aka Ghrelin Receptor) is an Allosteric Modulator of Dopamine Signaling in the Brain via Formation of GHSR1a:DRD2 and GHSR1a:DRD1 Heteromers

2014 ◽  
pp. 94-95
Author(s):  
Roy G. Smith ◽  
Celine Ullrich ◽  
Andras Kern
Keyword(s):  
Growth Hormone ◽  
Allosteric Modulator ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Dopamine Signaling ◽  
The Brain

scholarly journals Ghrelin Amplifies Dopamine Signaling by Cross Talk Involving Formation of Growth Hormone Secretagogue Receptor/Dopamine Receptor Subtype 1 Heterodimers

2006 ◽  
Vol 20 (8) ◽  
pp. 1772-1785 ◽  
Author(s):  
Hong Jiang ◽  
Lorena Betancourt ◽  
Roy G. Smith
Keyword(s):  
Dopamine Receptor ◽  
Fluorescent Protein ◽  
Green Fluorescent Protein Fluorescence ◽  
Receptor Subtype ◽  
Protein Fluorescence ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Dopamine Signaling

Abstract Our objective is to determine the neuromodulatory role of ghrelin in the brain. To identify neurons that express the ghrelin receptor [GH secretagogue receptor (GHS-R)], we generated GHS-R-IRES-tauGFP mice by gene targeting. Neurons expressing the GHS-R exhibit green fluorescence and are clearly evident in the hypothalamus, hippocampus, cortex, and midbrain. Using immunohistochemistry in combination with green fluorescent protein fluorescence, we identified neurons that coexpress the dopamine receptor subtype 1 (D1R) and GHS-R. The potential physiological relevance of coexpression of these two receptors and the direct effect of ghrelin on dopamine signaling was investigated in vitro. Activation of GHS-R by ghrelin amplifies dopamine/D1R-induced cAMP accumulation. Intriguingly, amplification involves a switch in G protein coupling of the GHS-R from Gα11/q to Gαi/o by a mechanism consistent with agonist-dependent formation of GHS-R/D1R heterodimers. Most importantly, these results indicate that ghrelin has the potential to amplify dopamine signaling selectively in neurons that coexpress D1R and GHS-R.

scholarly journals Genetic Linkage and Association of the Growth Hormone Secretagogue Receptor (Ghrelin Receptor) Gene in Human Obesity

Diabetes ◽  
2004 ◽  
Vol 54 (1) ◽  
pp. 259-267 ◽  
Author(s):  
A. Baessler ◽  
M. J. Hasinoff ◽  
M. Fischer ◽  
W. Reinhard ◽  
G. E. Sonnenberg ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Genetic Linkage ◽  
Receptor Gene ◽  
Human Obesity ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor

scholarly journals Expression of the growth hormone secretagogue receptor 1a (GHS‐R1a) in the brain

2021 ◽  
Vol 9 (21) ◽  
Author(s):  
Marat I. Airapetov ◽  
Sergei O. Eresko ◽  
Andrei A. Lebedev ◽  
Evgenii R. Bychkov ◽  
Petr D. Shabanov
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
The Brain

scholarly journals LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuehan Lu ◽  
Lili Huang ◽  
Zhengxiang Huang ◽  
Dandan Feng ◽  
Richard J. Clark ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Energy Balance ◽  
Food Intake ◽  
Antimicrobial Peptide ◽  
Molar Ratio ◽  
Positive Energy ◽  
Energy Status ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.

scholarly journals Evidence Supporting a Role for Constitutive Ghrelin Receptor Signaling in Fasting-Induced Hyperphagia in Male Mice

Endocrinology ◽  
2017 ◽  
Vol 159 (2) ◽  
pp. 1021-1034 ◽  
Author(s):  
Gimena Fernandez ◽  
Agustina Cabral ◽  
María F Andreoli ◽  
Alexandra Labarthe ◽  
Céline M'Kadmi ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Food Intake ◽  
Peptide Hormone ◽  
Negative Energy ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Orexigenic Peptide ◽  
Hypothalamic Arcuate Nucleus

Abstract Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein–coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone–releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance.

scholarly journals Expression of ghrelin or growth hormone secretagogue receptor in the brain of postpartum stress mice

Neuroreport ◽  
2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Jing-Wei Xing ◽  
Xin-Yun Tian ◽  
Man-Man Chen ◽  
Xiu-Hua Peng ◽  
Pengfei Gao
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Postpartum Stress ◽  
The Brain

scholarly journals Contribution of growth hormone secretagogue receptor (GHSR) signaling in the ventral tegmental area (VTA) to the regulation of social motivation in male mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Su-Bin Park ◽  
Samantha King ◽  
David MacDonald ◽  
Anne Wilson ◽  
Harry MacKay ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Ventral Tegmental Area ◽  
Social Motivation ◽  
Male Mice ◽  
Growth Hormone Secretagogue Receptor ◽  
Social Approach ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Ventral Tegmental ◽  
Motivated Behaviors

AbstractMost psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.

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