Ghrelin Through GHSR1a and OX1R Heterodimers Reveals a Gαs–cAMP-cAMP Response Element Binding Protein Signaling Pathway in Vitro

Xue, Qiao; Bai, Bo; Ji, Bingyuan; Chen, Xiaoyu; Wang, Chunmei; Wang, Peixiang; Yang, Chunqing; Zhang, Rumin; Jiang, Yunlu; Pan, Yanyou; Cheng, Baohua; Chen, Jing

doi:10.3389/fnmol.2018.00245

Cited by 29 publications

(24 citation statements)

References 48 publications

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“…In this study, using TM and TM‐m peptides as biochemical tools to dissect actions of the SCTR/AT1aR heteromer in PVN, we firstly demonstrate the in vivo actions of SCTR/AT1aR heteromer in regulating plasma Vp release and expression via cFos/cAMP/CREB pathway in magnocellular neurons of PVN. Our data also explain the results of previous studies indicating: 1 ) colocalization of SCTR and AT1aR in PVN, particularly in magnocellular neurons, 2) central actions of ANGII require an intact SCT‐SCTR axis, and 3) actions of the SCTR/AT1aR heteromer are largely dependent on the cAMP pathway (13, 36, 37). Of note, the functional specificity of SCTR/AT1aR heteromer was fully demonstrated by intracerebroventricular injection of STM2 because it can only disrupt SCTR/AT1aR heterodimerization but not SCTR or AT1aR homodimerization.…”

Section: Discussionsupporting

confidence: 91%

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

2019

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With an increasing body of evidence regarding GPCR oligomerization and its clinical implications over the last decade, the modulation and dynamics of GPCR homo‐ and hetero‐oligomers has more recently become an area of intense research focus. Previously, our lab showed in vitro heteromer formation between angiotensin II receptor type 1 subtype a (AT1aR) and secretin receptor (SCTR), which is involved in in vivo control of hyperosmolality‐induced water drinking behavior. Because the secretin (SCT)/SCTR axis is crucial to the central actions of angiotensin II (ANGII) and both SCT and ANGII are capable of triggering vasopressin (Vp) release from hypothalamus, we investigated here the in vivo role of SCTR‐AT1aR heteromer in regulating Vp release in hypothalamus using transmembrane peptides as tools. We showed that SCTR‐AT1aR heteromer mediates stimulatory actions of both SCT and ANGII in hypothalamic Vp expression and release as well as neuronal activities via the immediate early gene cFos. The results from this study not only are consistent with our hypothesis that SCT and ANGII interact at the receptor level to mediate their water homeostatic activities but also provide evidence for in vivo functions of cross‐class GPCR heteromers.—Mak, S. O. K., Zhang, L., Chow, B. K. C. In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN. FASEB J. 33, 5389–5398 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 91%

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

2019

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“…It has been reported that GPCRs can activate the PI3K/AKT signaling pathway. For example, orexin receptor (OXR) activation promotes the upregulation of a Gs-cAMP-cAMP-responsive element signaling pathway and plays a key role in the PI3K/AKT signaling pathway [ 52 , 53 ]. The succinate receptor GPR91, a Gi-coupled receptor, can increase intracellular calcium concentrations through PLCb and upregulate the levels of p-Akt/t-Akt in cardiomyocytes [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats

Chen

Sha

Wang

et al. 2020

J Neuroinflammation

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Background Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. Methods This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. Results In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. Conclusion Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.

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“…As a G-protein-coupled receptor, GHSR is present mainly existed in the hypothalamus and pituitary [9,28]. Two isoforms of GHSR have been reported [29], GHSR1α [30,31] and GHSR1β [32,33]. However, GHSR1α is responsible for ghrelin-induced endocrine effects and some nonendocrine effects.…”

Section: Ghsr1α Was Expressed In the Mouse Liver And Hepatocytesmentioning

confidence: 99%

Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

Luo

Yang

et al. 2020

Biol Trace Elem Res

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Background: The liver is the metabolic organ considered to contribute the most to maintaining body iron homeostasis and is a regulator of body adaptation to fasting. Our previous studies implied a negative relationship between iron and ghrelin in both mice and humans and indicated that ghrelin was able to increase ferroportin 1 (Fpn1) expression in the spleen and macrophages through the GHSR/MAPK pathway. However, it remains to be explored whether fasting or ghrelin has a functional effect on iron homeostasis in the liver. Methods: In this study, we examined the roles of fasting and ghrelin in modulating the protein expression of Fpn1, transferrin receptor 1 (TfR1), and ferritin light chain (Ft-L), as well as the mRNA expression of ghrelin, hepcidin, ghrelin O-acyltransferase (GOAT) and growth hormone secretagogue receptor 1 alpha (GHSR1α) in mouse liver and cultured hepatocytes. Results: Our in vivo results suggested that fasting significantly upregulated the mRNA expression of ghrelin, GOAT and GHSR1α as well as the protein levels of ghrelin, Fpn1 and Ft-L, but not TfR1, in mouse liver. Meanwhile, in cultured hepatocytes, ghrelin significantly increased the protein expression of Fpn1 but not Ft-L and TfR1 and significantly enhanced ERK phosphorylation. Furthermore, the pretreatment of cultured hepatocytes with either a pERK inhibitor or a GHSR1α antagonist abolished the effects of ghrelin on Fpn1 expression and ERK phosphorylation. Conclusions: Our findings confirmed that fasting increases iron export in the liver by upregulating Fpn1 expression through the ghrelin/GHSR1α/MAPK signaling pathway.

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Ghrelin Through GHSR1a and OX1R Heterodimers Reveals a Gαs–cAMP-cAMP Response Element Binding Protein Signaling Pathway in Vitro

Cited by 29 publications

References 48 publications

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats

Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

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