Affinage

GHSR

Growth hormone secretagogue receptor type 1 · UniProt Q92847

Length
366 aa
Mass
41.3 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GHSR (GHS-R1a) is a Gq/11-coupled receptor with high constitutive, ligand-independent activity that is an intrinsic property of the receptor protein itself, demonstrated by purified monomeric receptor in lipid discs activating Gq in the absence of agonist (PMID:22117076). Beyond canonical Gq/11-PLC-Ca2+ signaling, the receptor activates ERK1/2 through three parallel routes—a beta-arrestin-1/2-scaffolded complex with Src and Raf-1, a Gq/11-PKC-Src pathway, and a Gi-PI3K-PKC-Src pathway (PMID:17525997)—and these G protein- versus beta-arrestin-dependent arms are pharmacologically separable, as a biased small-molecule agonist can steer the receptor toward Galphaq activation over beta-arrestin recruitment (PMID:35239443). Signal termination depends on the distal C-terminal tail, which is required for beta-arrestin recruitment and internalization and acts as a physiological brake on ghrelin sensitivity in vivo (PMID:27095593). Receptor output is further tuned by oligomerization: the truncated isoform GHS-R1b traps GHS-R1a in the ER to attenuate surface expression and constitutive PLC activity (PMID:21903149), while heteromerization with D2R reshapes Galphai activation kinetics (PMID:29632174) and with 5-HT2C-INI attenuates calcium signaling (PMID:23161547). Constitutive activity has defined physiological roles: an activity-ablating mutation (A203E) removes the native depolarizing conductance of arcuate NPY neurons (PMID:32339772), and falling LEAP2 during fasting drives ghrelin-independent GHSR activation of PVH-CRF neurons (PMID:35504998). Through these pathways GHSR governs energy homeostasis and the somatotropic/HPA axes—regulating thermogenesis and adiposity via AgRP neurons (PMID:28420089), dopaminergic reward signaling via VTA GHS-R1a:GHS-R1b:D1R complexes (PMID:34876469), and glucose-stimulated insulin secretion cell-autonomously in pancreatic beta-cells through a non-canonical cAMP/TRPM2 pathway (PMID:26370322, PMID:33920473). Loss-of-function GHSR mutations cause short stature in humans (PMID:21084395).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 Medium

    Established how GHS-R1a converts ligand binding into ERK activation, defining multiple parallel transducer arms rather than a single pathway.

    Evidence Dominant-negative, siRNA, and pharmacological dissection with co-IP in HEK293 cells stably expressing GHS-R1a

    PMID:17525997

    Open questions at the time
    • Pathway dissection in a heterologous overexpression system, not native cells
    • Relative physiological weighting of the three arms unresolved
  2. 2010 Medium

    Linked GHSR to a human phenotype by showing that distinct loss-of-function mutations impair constitutive and/or agonist signaling in short-stature patients.

    Evidence Heterologous expression of four patient mutants with radioligand binding, surface-expression, and signaling assays

    PMID:21084395

    Open questions at the time
    • Causality at the individual-patient level not proven by family segregation in all cases
    • In vivo consequence of each mutation untested
  3. 2011 High

    Resolved whether GHSR's high constitutive activity is intrinsic to the protein or imposed by its cellular context, proving the monomeric receptor activates Gq without agonist.

    Evidence Reconstitution of purified GHS-R1a monomer in lipid discs with GTPgammaS binding, fluorescence, and arrestin-2/mu-AP2 co-recruitment

    PMID:22117076

    Open questions at the time
    • Does not address how constitutive activity is regulated in vivo
    • Structural basis of the constitutively active conformation not defined
  4. 2011 High

    Showed that the truncated GHS-R1b isoform acts as a negative regulator by ER-trapping GHS-R1a and reducing surface signaling.

    Evidence Reciprocal BRET, subcellular fractionation, immunocytochemistry, and PLC activity assays

    PMID:21903149

    Open questions at the time
    • Endogenous stoichiometry of GHS-R1a:GHS-R1b in native tissue unknown
    • Whether GHS-R1b levels are physiologically regulated not addressed
  5. 2012 Medium

    Extended GHSR regulation to heteromerization with other GPCRs, showing 5-HT2C-INI attenuates GHSR calcium signaling.

    Evidence Co-IP, BRET/FRET, calcium influx assay, and pharmacological rescue

    PMID:23161547

    Open questions at the time
    • Native co-expression and physiological context of these heteromers not established
    • Functional consequence of D1R and MC3R heteromers not quantified here
  6. 2015 Medium

    Defined a tissue-specific, non-canonical GHSR transducer by showing beta-cell GHSR couples to cAMP/TRPM2 to suppress insulin secretion and account for systemic glucose effects.

    Evidence Global GHSR-null mice with beta-cell-specific re-expression and in vivo glucose/insulin readouts

    PMID:26370322

    Open questions at the time
    • Molecular link between GHSR and cAMP/TRPM2 in beta-cells not fully mapped
    • Single lab
  7. 2016 Medium

    Established the distal C-terminal tail as the structural element required for signal termination and as a physiological suppressor of ghrelin sensitivity.

    Evidence Endogenous Ghsr(Q343X) rat mutation with cell-based G protein/beta-arrestin/internalization assays and in vivo phenotyping

    PMID:27095593

    Open questions at the time
    • Specific phosphorylation/recruitment sites within the tail not mapped
    • Single lab
  8. 2018 High

    Showed at the biochemical level how GHSR-D2R heteromerization modulates dopamine signaling by altering Galphai conformation and nucleotide kinetics.

    Evidence Reconstitution of purified GHSR-D2R tetramers in lipid environment with GTP-binding kinetics and stoichiometry determination

    PMID:29632174

    Open questions at the time
    • Native abundance of the tetramer in dopaminergic tissue not measured
    • Behavioral consequence not tested in this study
  9. 2020 High

    Demonstrated a physiological role for constitutive GHSR activity by ablating it with an A203E mutation and showing loss of the native depolarizing conductance of arcuate NPY neurons.

    Evidence GHSR-A203E knock-in mice with IP3 assays, CaV2.2 electrophysiology, and patch-clamp on hypothalamic neurons and slices

    PMID:32339772

    Open questions at the time
    • Downstream behavioral and metabolic phenotype of the knock-in not detailed here
    • Mechanism coupling constitutive activity to CaV2.2 not fully resolved
  10. 2021 High

    Identified the receptor oligomer mediating ghrelin's dopaminergic effects, defining GHS-R1a:GHS-R1b:D1R trimers in the VTA with Gs coupling.

    Evidence Co-IP/BRET in transfected cells, ex vivo MAPK assay, in vivo microdialysis, and VTA patch-clamp

    PMID:34876469

    Open questions at the time
    • Endogenous trimer abundance and regulation in VTA not quantified
    • How Gs coupling arises from a Gq-biased receptor not mechanistically explained
  11. 2021 Medium

    Confirmed beta-cell GHSR cell-autonomously regulates glucose-stimulated insulin secretion and systemic insulin sensitivity.

    Evidence Beta-cell-specific conditional Ghsr knockout mice with in vivo and ex vivo GSIS, ITT, and GHSR reporter

    PMID:33920473

    Open questions at the time
    • Reconciliation of inhibitory ghrelin and stimulatory obestatin signaling through the same receptor not resolved
    • Single lab
  12. 2022 Medium

    Proved that GHSR G protein- and beta-arrestin-dependent signaling are pharmacologically separable using a biased agonist that favors Galphaq.

    Evidence High-throughput screening, SAR, biased-agonism pathway assays, and in vivo dopaminergic behavior in mice

    PMID:35239443

    Open questions at the time
    • Structural basis of conformational bias not defined
    • Therapeutic window and selectivity in vivo not fully characterized
  13. 2022 Medium

    Dissected ghrelin-independent constitutive GHSR signaling in fasting, showing LEAP2 withdrawal drives PVH-CRF neuron activation independent of ghrelin itself.

    Evidence GHSR-KO, ghrelin-deleted mice, arcuate ablation, central GHSR-ligand blockade, and continuous LEAP2 infusion with c-Fos/CRF immunostaining

    PMID:35504998

    Open questions at the time
    • Circuit connecting arcuate GHSR to PVH-CRF neurons not fully mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How tissue context selects among GHSR's transducer repertoire (Gq/11, Gi, Gs, beta-arrestin, cAMP/TRPM2) and how constitutive versus ligand-driven activity are balanced in each cell type remains unresolved.
  • No unified structural model linking receptor conformation to pathway choice across tissues
  • Endogenous abundance and regulation of the various heteromers in native tissue largely unmeasured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
ARRB1ARRB2DRD1DRD2GHSR (GHS-R1B)HTR2CMC3R
Complex memberships
GHS-R1a:GHS-R1b heterodimerGHS-R1a:GHS-R1b:D1R oligomerGHSR:D2R heterotetramer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Purified monomeric GHS-R1a reconstituted in lipid discs constitutively activates Gq protein (measured by GTPγS binding) in the absence of agonist, demonstrating that high constitutive activity is an intrinsic property of the receptor protein itself rather than a consequence of its cellular environment. The isolated receptor also recruits arrestin-2 in an agonist-dependent manner but interacts with μ-AP2 in the absence of ligand or in the presence of ghrelin, indicating ligand-specific receptor conformations. Reconstitution of purified GHS-R1a monomer in lipid discs; GTPγS binding assay; intrinsic fluorescence measurements; co-recruitment assays with arrestin-2 and μ-AP2 The Journal of biological chemistry High 22117076
2018 Purified GHSR and D2R assemble in a lipid environment as a tetrameric complex (two each of the two receptors) that recruits only two Gαi trimers per tetramer. Receptor heteromerization directly modulates dopamine-mediated Gi protein activation by altering the conformation of the Gαi α-subunit, resulting in a higher rate of GTP binding and faster dissociation from the heteromeric receptor. Reconstitution with purified receptors in lipid environment; GTP binding kinetics; Gαi conformational analysis; receptor complex stoichiometry determination Proceedings of the National Academy of Sciences of the United States of America High 29632174
2011 The truncated isoform GHS-R1b localizes primarily in the endoplasmic reticulum (ER) and forms heterodimers with GHS-R1a. GHS-R1b traps GHS-R1a within the ER through oligomerization (demonstrated by BRET showing GHS-R1a/GHS-R1b heterodimers concentrated in ER fractions), thereby decreasing GHS-R1a plasma membrane expression and attenuating constitutive phospholipase C activation. Bioluminescence resonance energy transfer (BRET); immunocytochemistry; subcellular fractionation; functional PLC activity assays Molecular and cellular endocrinology High 21903149
2007 GHS-R1a activates ERK1/2 via three distinct pathways in HEK293 cells: (1) a β-arrestin-1/2-dependent pathway requiring a multiprotein complex with β-arrestins, Src, Raf-1, and ERK1/2; (2) a Gq/11-dependent pathway involving Ca2+-dependent PKCα/β and Src; and (3) a Gi-dependent pathway involving PI3K, PKCε, and Src. Gi/o and Gq/11 proteins are also required for β-arrestin-mediated ERK1/2 activation. Dominant-negative and siRNA knockdown of signaling components; pharmacological inhibitors; co-immunoprecipitation of signaling complexes in HEK293 cells stably expressing GHS-R1a Journal of cellular physiology Medium 17525997
2012 GHS-R1a forms heterodimers with D1R, MC3R, and 5-HT2C receptors. Heterodimerization with the unedited 5-HT2C-INI isoform (but not the partially edited 5-HT2C-VSV isoform) significantly reduced GHS-R1a agonist-mediated calcium influx; this reduction was completely restored by pharmacological blockade of 5-HT2C, indicating that 5-HT2C-INI heterodimerization attenuates GHS-R1a signaling. Co-immunoprecipitation; BRET/FRET dimerization assays; calcium influx functional assay; pharmacological blockade experiments The Journal of biological chemistry Medium 23161547
2008 Growth hormone-releasing hormone (GHRH) acts as an agonist at GHS-R1a: GHRH induces dose-dependent calcium mobilization and inositol phosphate turnover in HEK293 cells expressing GHS-R1a (but not wild-type HEK293 cells). Radioligand binding and cross-linking studies confirmed GHRH acts through GHS-R1a. GHRH increases 125I-ghrelin binding capacity with positive cooperativity, activates GHS-R1a endocytosis, and GHRH-R antagonists also function as GHS-R1a antagonists. Radioligand binding; cross-linking studies; calcium mobilization assay; inositol phosphate turnover assay; confocal microscopy of GHS-R1a-eGFP endocytosis in CHO cells Proceedings of the National Academy of Sciences of the United States of America Medium 19088192
2015 In pancreatic β-cells, ghrelin inhibits glucose-induced insulin secretion through GHS-R coupled to a novel cAMP/TRPM2 signaling pathway (rather than the canonical Gq/11 pathway used in other tissues). Using GHSR-null mice with β-cell-specific GHSR re-expression, this β-cell GHSR-cAMP/TRPM2 signaling was shown to largely account for the systemic effects of ghrelin on circulating glucose and insulin levels. Global GHSR knockout mice; β-cell-specific GHSR re-expression mice; in vivo glucose/insulin measurements; pharmacological pathway dissection Scientific reports Medium 26370322
2010 Four novel GHSR1A mutations identified in Japanese short-stature patients (ΔQ36, P108L, C173R, D246A) have varying loss-of-function effects on constitutive signaling. C173R causes intracellular retention of the receptor (total loss of function); P108L reduces ghrelin-binding affinity without affecting surface expression; D246A impairs both agonist- and inverse agonist-stimulated signaling; ΔQ36 shows only subtle reduction in constitutive activity. Heterologous expression of mutant receptors; radioligand binding assay; constitutive and agonist-induced signaling assays; surface expression analysis The Journal of clinical endocrinology and metabolism Medium 21084395
2016 In rats with the Ghsr(Q343X) mutation deleting the distal C-terminal tail, GHSR-Q343X shows enhanced ligand-induced G protein-dependent signaling and blunted β-arrestin recruitment and receptor internalization compared to wild-type GHSR, demonstrating that the distal C-terminal domain is required for signal termination (receptor internalization and β-arrestin recruitment) and acts as a physiological suppressor of ghrelin sensitivity in vivo. Site-specific mutation in rats (Ghsr(Q343X)); cell-based signaling assays (G protein activation, β-arrestin recruitment, internalization); in vivo ghrelin dose-response; metabolic phenotyping Science signaling Medium 27095593
2020 The GHSR-A203E mutation (corresponding to human A204E) ablates constitutive (ghrelin-independent) GHSR activity: in COS-7 cells, GHSR-A203E shows lower baseline IP3 than wild-type GHSR; in HEK293T cells co-transfected with CaV2.2 calcium channels, GHSR-A203E does not suppress basal CaV2.2 current (unlike wild-type GHSR which does). In cultured hypothalamic neurons and brain slices, constitutive GHSR activity contributes to the native depolarizing conductance of arcuate NPY neurons, with GHSR-A203E neurons showing greater native calcium currents and hyperpolarized resting membrane potentials of arcuate NPY neurons compared to wild-type. GHSR-A203E knock-in mice; IP3 accumulation assay; patch-clamp electrophysiology on cultured hypothalamic neurons and brain slices; CaV2.2 current density assay in HEK293T cells Molecular metabolism High 32339772
2021 GHS-R1a:GHS-R1b:D1R oligomeric complexes in the ventral tegmental area (VTA) serve as the predominant mediators of ghrelin's dopaminergic effects. In transfected cells, these trimeric complexes show Gs coupling and are pharmacologically distinct from GHS-R1a:GHS-R1b:D5R oligomers. In rodent VTA, ghrelin activates dopaminergic neurons via MAPK signaling, increases somatodendritic dopamine release (microdialysis), and depolarizes dopaminergic cells (patch-clamp), effects blocked by both GHS-R1a and D1R antagonists. Co-immunoprecipitation/BRET in transfected cells; ex vivo MAPK activation assay; in vivo microdialysis; patch-clamp electrophysiology in VTA The Journal of neuroscience High 34876469
2009 Peripheral ghrelin infusion increases retroperitoneal and inguinal white adipose tissue (WAT) mass in rats through GHS-R1a-dependent lipid retention (reduced lipid export via decreased ABCG1 expression and circulating free fatty acids), without altering food intake, adipogenesis markers, or substrate uptake markers. Ghrelin also induces hepatic steatosis (increased lipid droplet number and triacylglycerol) via a GHS-R1a-dependent mechanism. The effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R1a; unacylated ghrelin had no effect. Chronic iv infusion in rats; GHS-R1a transcriptional blockade; microarray analysis; lipid transport and synthesis marker measurement Molecular endocrinology Medium 19299444
2017 GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake, and adiposity. AgRP-neuron-specific GHS-R knockout mice show attenuated diet-induced obesity and enhanced thermogenic activation in brown and subcutaneous fat on high-fat diet, implying that GHS-R suppression in AgRP neurons enhances sympathetic outflow to adipose tissue. AgRP neuron-specific Cre-mediated GHS-R knockout (AgRP-Cre;Ghsr mice); metabolic phenotyping; thermogenic gene expression in adipose; indirect calorimetry International journal of molecular sciences Medium 28420089
2021 β-cell-specific GHSR deletion (MIP-Cre/ERT;Ghsr f/f mice) results in lower fasting blood glucose and insulin, reduced first-phase insulin secretion during GTT, and reduced GSIS both in vivo and in isolated islets ex vivo, and improved insulin sensitivity. This demonstrates that β-cell GHS-R cell-autonomously regulates glucose-stimulated insulin secretion and systemic insulin sensitivity. β-cell-specific conditional knockout mice; GTT/GSIS in vivo; isolated islet GSIS ex vivo; insulin tolerance test; GHSR-tauGFP reporter to confirm expression in β and α cells International journal of molecular sciences Medium 33920473
2017 Obestatin stimulates glucose-stimulated insulin secretion (GSIS) through GHS-R in pancreatic β-cells. Obestatin-induced GSIS was absent in β-cells with suppressed GHS-R, abolished in Ghsr-/- mice in vivo and in isolated islets from Ghsr-/- mice ex vivo, and attenuated in β-cell-specific Ghsr knockout islets. This demonstrates that obestatin, despite being encoded by the same preproghrelin gene as ghrelin, has opposite effects on insulin secretion, both mediated through GHS-R. GHS-R siRNA knockdown in INS-1 cells; global Ghsr-/- mice; β-cell-specific Ghsr knockout mice (MIP-Cre/ERT;Ghsr f/f); GSIS assay in vivo and ex vivo Scientific reports Medium 28428639
2022 Food deprivation-induced activation of CRF-producing neurons of the hypothalamic paraventricular nucleus (PVH-CRF neurons) requires GHSR signaling at the hypothalamic level but not ghrelin itself. The fall in plasma LEAP2 during food deprivation (which upregulates GHSR constitutive/ghrelin-independent activity) is necessary for PVH-CRF neuron activation; continuous systemic LEAP2 infusion prevents this neuronal activation during fasting without affecting body weight or blood glucose. GHSR knockout mice; ghrelin gene-deleted mice; arcuate nucleus neurotoxic ablation; anti-ghrelin antibody central infusion; GHSR-ligand central injection blocking both ghrelin-evoked and constitutive GHSR activities; continuous LEAP2 systemic infusion; c-Fos/CRF immunostaining Cellular and molecular life sciences Medium 35504998
2013 GHS-R1a knockdown in the dorsomedial hypothalamus (DMH) reduces food anticipatory activity (FAA) amplitude and delays FAA onset under restricted feeding. GHS-R1a knockdown in the ventromedial hypothalamus (VMH) increases food intake and body weight under ad libitum conditions and also reduces FAA. These results implicate hypothalamic DMH and VMH GHS-R1a signaling in the regulation of food anticipatory activity. Adeno-associated virus shRNA-mediated local GHS-R1a knockdown in DMH and VMH in rats; restricted feeding behavioral paradigm; measurement of running wheel activity and food anticipatory locomotion International journal of obesity Medium 23884084
2012 GHSR colocalization with GH (somatotrophs), ACTH (corticotrophs), PRL (lactotrophs), LH (gonadotrophs), and TSH (thyrotrophs) in the anterior pituitary was directly mapped using a GHSR-eGFP reporter mouse. 77% of somatotrophs expressed GHSR-eGFP. Calorie restriction suppressed GHSR-eGFP expression on lactotrophs and gonadotrophs but increased it on thyrotrophs. GHSR expression was higher in male than female pituitary. GHSR-eGFP reporter mouse; double immunofluorescence staining with anterior pituitary hormone antibodies; quantitative cell counting Endocrinology Medium 22962259
2020 GHSR deficiency in macrophages instigates NLRP3 inflammasome activation with increased cleavage and release of interleukin-18. GHSR deficiency in cardiac fibroblasts increases myofibroblast trans-differentiation marker expression (α-SMA, SM22, calponin) upon TGF-β treatment. In vivo, GHSR deficiency exacerbates isoproterenol-induced cardiac fibrosis and activates Wnt/β-catenin signaling. GHSR-/- mice; isoproterenol-induced cardiac fibrosis model; isolated cardiac fibroblasts from GHSR-/- mice; western blotting; immunofluorescence; RNA-sequencing of heart transcriptomes Cardiovascular research Medium 31790138
2009 GHS-R1a mediates ghrelin's inhibitory effect on gastric acid secretion: the GHS-R1a agonist EP1572 (but not des-octanoyl ghrelin, which does not bind hypothalamic GHS-R1a) inhibits gastric acid secretion, and the GHS-R1a antagonist D-Lys3-GHRP-6 abolishes ghrelin-induced gastric acid inhibition. This was confirmed by receptor binding displacement assays showing D-Lys3-GHRP-6 binds hypothalamic GHS-R, whereas des-octanoyl ghrelin does not. Central (icv) pharmacological administration in pylorus-ligated rats; radioligand displacement binding assay on rat hypothalamic membranes; measurement of gastric acid volume and output Journal of neuroendocrinology Medium 16420281
2006 Adenosine does not bind to GHS-R1a and is not an agonist of GHS-R1a. The number of adenosine-binding sites is identical in HEK293 wild-type cells and HEK-GHS-R1a cells; this binding is unaffected by GHS-R1a antagonists. Adenosine fails to induce GHS-R1a endocytosis and acts through endogenous adenosine receptor subtypes 2b and 3 (which are equally expressed in both cell lines), though it can partially attenuate ghrelin-induced GHS-R1a endocytosis. Radioligand binding assay in HEK293 and HEK-GHS-R1a cells; Western blot for adenosine receptor expression; calcium mobilization assay; receptor endocytosis assay; PKC sensitivity comparison The Journal of endocrinology Medium 17065398
2019 Ghrelin attenuates neuronal apoptosis and oxidative stress after hypoxic-ischemic injury via the GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 signaling pathway. The protective effects (improved neurobehavioral outcomes, reduced oxidative stress markers, increased Bcl-2/Bax ratio, decreased cleaved caspase-3) were reversed by GHSR-1α siRNA knockdown or GHSR-1α antagonist [D-Lys3]-GHRP-6, demonstrating GHSR-1α dependence. Neonatal rat HI model; intranasal ghrelin administration; GHSR-1α siRNA icv injection; GHSR-1α antagonist [D-Lys3]-GHRP-6; western blot; TUNEL staining; immunofluorescence Free radical biology & medicine Medium 31279091
2011 Ghrelin increases glioma cell migration through GHS-R-mediated activation of CaMKII, AMPK, and NF-κB signaling pathways. Ghrelin increases GHS-R expression in glioma cells; GHS-R antagonist blocks migration. CaMKII inhibitor, AMPK inhibitor/siRNA, and NF-κB inhibitors or dominant-negative IKKα/IKKβ all reduce ghrelin-induced migration. Ghrelin increases phosphorylation of CaMKII, AMPK, IKKα/β, IκBα, and p65, and increases NF-κB-DNA binding activity. C6 and U251 glioma cell migration assay; pharmacological inhibitors; AMPK siRNA; dominant-negative kinase constructs; western blot; NF-κB reporter assay Journal of cellular biochemistry Low 21630326
2016 Ghrelin induces colon cancer cell (HT-29) proliferation through GHS-R, activating Ras/PI3K/Akt/mTOR signaling. GHS-R inhibitor [D-Lys3]-GHRP-6 reduces proliferation. Dominant-negative Ras, PI3K inhibitor LY294002, dominant-negative Akt, and mTOR inhibitor rapamycin all attenuate ghrelin-induced proliferation. Ghrelin induces Ras activity and Akt Ser473 and mTOR Ser2448 phosphorylation in a Ras- and PI3K-dependent manner. HT-29 proliferation assay; pharmacological inhibitors; dominant-negative Ras and Akt constructs; kinase activity assays; western blot for phosphorylation European journal of pharmacology Low 26879868
2022 A brain-penetrant small molecule (N8279/NCATS-SM8864) biases GHSR1a conformations toward Gαq activation (functionally selective agonism) rather than β-arrestin recruitment, demonstrating pharmacologically separable G protein- and β-arrestin-dependent signaling pathways downstream of GHSR1a. N8279 reduces aberrant dopaminergic behavior in mice. High-throughput screening; structure-activity relationship studies; biased agonism assays (Gαq vs. β-arrestin pathway); in vivo dopaminergic behavior in mice Proceedings of the National Academy of Sciences of the United States of America Medium 35239443
2017 Fasting upregulates ferroportin 1 (Fpn1) expression in mouse spleen via a ghrelin/GHSR/MAPK signaling pathway. Ghrelin increases Fpn1 and ferritin light chain protein expression in macrophages in vitro, induces phosphorylation of ERK and translocation of pERK to nuclei. Increased pERK and Fpn1 induced by ghrelin are prevented by pre-treatment with either GHSR1α antagonist or pERK inhibitor. In vivo fasting in mice; in vitro macrophage culture with ghrelin; GHSR1α antagonist pretreatment; pERK inhibitor; western blot for iron metabolism proteins and pERK; nuclear fractionation Journal of cellular physiology Low 28338217

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. The Journal of clinical endocrinology and metabolism 1150 12050285
1997 Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat. Endocrinology 167 9348177
2006 Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a. The Journal of endocrinology 140 16394173
2009 Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention. Molecular endocrinology (Baltimore, Md.) 132 19299444
2011 High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. The Journal of biological chemistry 125 22117076
2012 Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. The Journal of biological chemistry 110 23161547
2001 Generation of polyclonal antiserum against the growth hormone secretagogue receptor (GHS-R): evidence that the GHS-R exists in the hypothalamus, pituitary and stomach of rats. Life sciences 108 11212874
2011 Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addiction biology 101 21309944
2019 Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE. Free radical biology & medicine 98 31279091
2013 Ghrelin receptor (GHS-R1A) antagonism suppresses both alcohol consumption and the alcohol deprivation effect in rats following long-term voluntary alcohol consumption. PloS one 85 23977009
2008 Association of pro-ghrelin and GHS-R1A gene polymorphisms and haplotypes with heavy alcohol use and body mass. Alcoholism, clinical and experimental research 71 18828808
2011 The truncated ghrelin receptor polypeptide (GHS-R1b) is localized in the endoplasmic reticulum where it forms heterodimers with ghrelin receptors (GHS-R1a) to attenuate their cell surface expression. Molecular and cellular endocrinology 70 21903149
2001 Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas. Clinical endocrinology 64 11422110
2010 Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides 63 20804798
2009 Association and interaction analyses of genetic variants in ADIPOQ, ENPP1, GHSR, PPARgamma and TCF7L2 genes for diabetic nephropathy in a Taiwanese population with type 2 diabetes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 63 19506043
2019 The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice. Neuropharmacology 62 31103617
2013 GHS-R1a constitutive activity and its physiological relevance. Frontiers in neuroscience 62 23754971
2009 Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats. European journal of pharmacology 60 19356720
2011 Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes. Journal of cellular biochemistry 59 21268092
2019 Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity. Trends in endocrinology and metabolism: TEM 57 31636018
2016 Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways. European journal of pharmacology 56 26879868
2010 Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. The Journal of clinical endocrinology and metabolism 55 21084395
2011 Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-κB signaling pathway in glioma cells. Journal of cellular biochemistry 54 21630326
2018 GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation. Proceedings of the National Academy of Sciences of the United States of America 53 29632174
2011 The ghrelin/GOAT/GHS-R system and energy metabolism. Reviews in endocrine & metabolic disorders 51 21340583
2017 Clarifying the Ghrelin System's Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand. International journal of molecular sciences 50 28422060
2015 The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin. Scientific reports 50 26370322
2013 Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway. American journal of physiology. Endocrinology and metabolism 50 24326424
2007 Stimulation by ghrelin of p42/p44 mitogen-activated protein kinase through the GHS-R1a receptor: role of G-proteins and beta-arrestins. Journal of cellular physiology 50 17525997
2015 A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 49 26508707
2012 Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory. Behavioural brain research 49 22484009
2017 Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis. International journal of molecular sciences 45 28420089
2015 Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naïve male mice. Psychoneuroendocrinology 42 26398679
2009 Ghrelin receptor (GHS-R)-like receptor and its genomic organisation in rainbow trout, Oncorhynchus mykiss. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 40 19361568
2008 Expression of ghrelin receptor, GHSR-1a, and its functional role in the porcine ovarian follicles. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 40 18809347
2020 GHSR deficiency exacerbates cardiac fibrosis: role in macrophage inflammasome activation and myofibroblast differentiation. Cardiovascular research 37 31790138
2016 Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats. Scientific reports 37 27271793
2012 Ghrelin receptor expression and colocalization with anterior pituitary hormones using a GHSR-GFP mouse line. Endocrinology 37 22962259
2008 Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. Proceedings of the National Academy of Sciences of the United States of America 37 19088192
2020 Metabolic insights from a GHSR-A203E mutant mouse model. Molecular metabolism 36 32339772
2012 MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation? Neuroendocrinology 36 22327910
2012 Molecular identification of GHS-R and GPR38 in Suncus murinus. Peptides 36 22579813
2015 Differential gene regulation of GHSR signaling pathway in the arcuate nucleus and NPY neurons by fasting, diet-induced obesity, and 17β-estradiol. Molecular and cellular endocrinology 35 26577678
2011 Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a. Investigative ophthalmology & visual science 35 21642627
2014 Ghrelin alleviates neuropathic pain through GHSR-1a-mediated suppression of the p38 MAPK/NF-κB pathway in a rat chronic constriction injury model. Regional anesthesia and pain medicine 34 24513955
2019 Fasting Upregulates npy, agrp, and ghsr Without Increasing Ghrelin Levels in Zebrafish (Danio rerio) Larvae. Frontiers in physiology 33 30733682
2021 Performance of DNA methylation analysis of ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1 and SST for the triage of HPV-positive women: Results from a Dutch primary HPV-based screening cohort. International journal of cancer 32 34558659
2009 Associations of GHSR gene polymorphisms with chicken growth and carcass traits. Molecular biology reports 32 19437137
2023 Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. Neuropharmacology 31 37369277
2011 Molecular identification of ghrelin receptor (GHS-R1a) and its functional role in the gastrointestinal tract of the guinea-pig. Peptides 31 21843569
2022 GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner. Cellular and molecular life sciences : CMLS 30 35504998
2012 The growth hormone secretagogue receptor (Ghs-R). Current pharmaceutical design 30 22632856
2019 GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress. Frontiers in neuroscience 28 31057357
2015 GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers. Oncotarget 28 25557172
2011 Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides 28 21930173
2007 Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging. Annals of the New York Academy of Sciences 27 18056963
2006 Evidence for a role of the GHS-R1a receptors in ghrelin inhibition of gastric acid secretion in the rat. Journal of neuroendocrinology 27 16420281
2019 DNA methylation of GHSR, GNG4, HOXD9 and SALL3 is a common epigenetic alteration in thymic carcinoma. International journal of oncology 26 31746370
2015 Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles. Physiology & behavior 26 26723269
2014 Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists. Journal of medicinal chemistry 25 24967667
2009 Associations of polymorphism within the GHSR gene with growth traits in Nanyang cattle. Molecular biology reports 25 19148773
2013 The ghrelin receptors (GHS-R1a and GHS-R1b). Endocrine development 24 23652387
2013 GHS-R1a signaling in the DMH and VMH contributes to food anticipatory activity. International journal of obesity (2005) 24 23884084
2011 The GHS-R blocker D-[Lys3] GHRP-6 serves as CCR5 chemokine receptor antagonist. International journal of medical sciences 23 22211090
2017 Obestatin stimulates glucose-induced insulin secretion through ghrelin receptor GHS-R. Scientific reports 22 28428639
2021 High Coexpression of the Ghrelin and LEAP2 Receptor GHSR With Pancreatic Polypeptide in Mouse and Human Islets. Endocrinology 21 34289060
2019 Acute But Not Chronic Calorie Restriction Defends against Stress-Related Anxiety and Despair in a GHS-R1a-Dependent Manner. Neuroscience 21 31185255
2016 GHSR-1a is a novel pro-angiogenic and anti-remodeling target in rats after myocardial infarction. European journal of pharmacology 21 27343377
2021 Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D1 Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin. The Journal of neuroscience : the official journal of the Society for Neuroscience 20 34876469
2016 Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite. Science signaling 20 27095593
2008 Differential expression of ghrelin and its receptor (GHS-R1a) in various adrenal tumors and normal adrenal gland. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 20 18246525
2017 Fasting up-regulates ferroportin 1 expression via a Ghrelin/GHSR/MAPK signaling pathway. Journal of cellular physiology 19 28338217
2014 Assessing interactions between Ghsr and Mc3r reveals a role for AgRP in the expression of food anticipatory activity in male mice. Endocrinology 19 25211592
2014 Potential new role of the GHSR-1a-mediated signaling pathway in cardiac remodeling after myocardial infarction (Review). Oncology letters 18 25120643
2009 Ghrelin stimulation of gonadotropin (LH) release from goldfish pituitary cells: presence of the growth hormone secretagogue receptor (GHS-R1a) and involvement of voltage-sensitive Ca2+ channels. Molecular and cellular endocrinology 18 20036709
2021 Genetic deletion of the ghrelin receptor (GHSR) impairs growth and blunts endocrine response to fasting in Ghsr-IRES-Cre mice. Molecular metabolism 17 33798772
2021 Expression of the growth hormone secretagogue receptor 1a (GHS-R1a) in the brain. Physiological reports 17 34755494
2020 Neuropeptide receptor genes GHSR and NMUR1 are candidate epigenetic biomarkers and predictors for surgically treated patients with oropharyngeal cancer. Scientific reports 17 31974445
2020 The new mechanism of Ghrelin/GHSR-1a on autophagy regulation. Peptides 17 31981593
2016 Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish. General and comparative endocrinology 17 26773340
2011 Effect of inhibitor and activator of ghrelin receptor (GHS-R1a) on porcine ovarian granulosa cell functions. General and comparative endocrinology 17 21600209
2022 Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proceedings of the National Academy of Sciences of the United States of America 16 35239443
2018 Obesity as the Sequel of Childhood Stunting: Ghrelin and GHSR Gene Polymorphism Explained. Acta medica Indonesiana 16 29950536
2013 The expression of GHS-R in primary neurons is dependent upon maturation stage and regional localization. PloS one 16 23755116
2012 Diagnostic values of GHSR DNA methylation pattern in breast cancer. Breast cancer research and treatment 16 22899222
2008 A genetic study of the ghrelin and growth hormone secretagogue receptor (GHSR) genes and stature. Annals of human genetics 16 18945286
2021 β Cell GHS-R Regulates Insulin Secretion and Sensitivity. International journal of molecular sciences 15 33920473
2020 Rapid and Prolonged Antidepressant-like Effect of Crocin Is Associated with GHSR-Mediated Hippocampal Plasticity-related Proteins in Mice Exposed to Prenatal Stress. ACS chemical neuroscience 15 32203651
2015 Sex biased expression of ghrelin and GHSR associated with sexual size dimorphism in yellow catfish. Gene 15 26692148
2006 Adenosine does not bind to the growth hormone secretagogue receptor type-1a (GHS-R1a). The Journal of endocrinology 15 17065398
2021 GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis. International journal of obesity (2005) 14 33903722
2019 GHSR DNA hypermethylation is a new epigenetic biomarker for gastric adenocarcinoma and beyond. Journal of cellular physiology 14 30677130
2016 Rats with a truncated ghrelin receptor (GHSR) do not respond to ghrelin, and show reduced intake of palatable, high-calorie food. Physiology & behavior 14 27129673
2017 Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons. Molecular neurobiology 13 28717967
2014 Central injection of urocortin-3 but not corticotrophin-releasing hormone influences the ghrelin/GHS-R1a system of the proventriculus and brain in chicks. Domestic animal endocrinology 13 24484650
2024 Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet. Communications biology 12 38796563
2021 Contribution of growth hormone secretagogue receptor (GHSR) signaling in the ventral tegmental area (VTA) to the regulation of social motivation in male mice. Translational psychiatry 12 33879778
2014 Molecular cloning, regulation, and functional analysis of two GHS-R genes in zebrafish. Experimental cell research 12 24928276
2007 The hepatocarcinoma cell line HepG2 does not express a GHS-R1a-type ghrelin receptor. Journal of receptor and signal transduction research 12 17885924
2018 Investigation of GHSR and GHRL methylation in colorectal cancer. Epigenomics 11 29963901

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