Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Gastrin-Releasing Peptide Receptor (GRPR)

  • Alessia Parascandolo
  • Maria Domenica Castellone
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101646


Historical Background

The human gastrin-releasing peptide receptor (hGRPR) gene was cloned in 1990 from NIH3T3 cells and located on chromosome X (Xp22.2–Xp22.13). It encodes a seven-transmembrane α-helices G protein-coupled receptor (GPCR) of 384-aa, interacting with large heterotrimeric G proteins of the Gαq and Gα12/ Gα13 families. The main GRPR ligands are represented by bombesin-like peptides (BLPs), including gastrin-releasing peptide (GRP) that is a peptide originally isolated from porcine stomach, synthesized as a precursor of 148-aa (PreproGRP) and post-translationally modified as a mature 27-aa neuropeptide. GRP is the mammalian homolog of the amphibian 14-aa peptide bombesin (BBS), sharing the same C-terminal sequence and binding to the same receptor. Four BLP binding receptor subtypes have been isolated: receptor subtype 1, termed GRPR, which binds BBS and GRP with high affinity; receptor subtype 2 binding neuromedin B; subtype 3 classified as an orphan receptor; and subtype 4, binding amphibian BBS with higher affinity than GRP. In humans, ligands and receptors are widely distributed, and their expression levels are high during embryonic formation, while they decrease at birth, being mainly located in the central nervous system (CNS) and neuroendocrine system (thyroid, pituitary glands, pancreas, adrenal glands) as well as in several peripheral tissues including the gastrointestinal tract, lungs, muscles, urogenital and reproductive system, immune cells, and hematopoietic system. In CNS, BLPs/GRPR function as neurotransmitters to control thermoregulation, feeding behavior, circadian rhythm, memory, as well as social interaction and emotional responses (Roesler et al. 2006); in the gastrointestinal tract, they control the release of gastrointestinal hormones (Jensen et al. 1988); in muscles they regulate smooth muscle cell contraction (Severi et al. 1991), while in epithelial cells they control cell proliferation (Ghatei et al. 1982). Interestingly, the biological effects resulting from the binding of GRPR to its ligand are quite often mediated by the release of secondary peptide hormones, for instance, GRP stimulation of GRPR on gastric G-cells mediates gastrin release and gastric acid secretion from parietal cells (Weigert et al. 1996); GRP stimulation of pancreatic cells modulates amylase secretion (Jensen et al. 1988), whereas BBS activation of M-cells in the small intestine results in the secretion of motilin and regulation of smooth muscle cell contraction (Poitras et al. 1997).

GRPR-Mediated Signaling

GRPR couples to G proteins of the Gαq and Gα12/Gα13 families. Upon ligand binding, GRPR undergoes a conformational change that catalyzes the dissociation from GDP (off-state) and the binding to GTP (on-state) with recruitment of the Gαq/Gα12–Gα13 subunit of large G protein and consequent dissociation of the Gβγ subunits. Gαq binding activates phospholipase C-β (PLC-β) signaling pathway which leads to calcium elevation, protein kinase C (PKC) stimulation, and mitogen-activated protein (MAP) kinase pathways activation (Helmich et al. 1999), while Gα12/Gα13 activation results in small GTPase Rho signaling that leads to the activation of c-Jun N-terminal kinase (JNK) and p38 that together with the MAPK converge on several transcription factors to promote survival and proliferative signals. On the other hand, Rho activation induces stress fiber formation, cytoskeleton remodeling, and cell adhesion, through involvement of ROCK and FAK kinases therefore regulating cell migration and adhesion (Siehler 2009; Kurose 2003) (Fig. 1). Activation of Rho has also been involved in cellular immunological processes promoting neutrophils, monocytes, and fibroblast migration (Zheng et al. 2006).
Gastrin-Releasing Peptide Receptor (GRPR), Fig. 1

Molecular mechanisms mediating GRPR signaling. GRP/BBS ligand binding activates a signal transduction mediated by Gαq/Gα12-Gα13 and resulting in regulation of cell proliferation, survival, and differentiation (through MAPK, JNK, p38 kinases) as well as in cytoskeleton remodeling, induction of migration, and adhesion (through ROCK, FAK kinases)

GRPR Expression in Human Diseases

The central nervous system (CNS) together with the gastrointestinal system (GI) represents the locations with higher GRPR levels; therefore, BBS/GRPR signaling has been involved in a variety of nervous and neuroendocrine functions. Recent evidences have suggested that GRPR-mediated signaling in CNS could function as regulator of behavior, social interaction, memory, emotional responses, and food intake, while dysfunctions of BBS/GRPR system have been related to neurodegenerative disorders, memory alterations, anxiety, and autism. The role of GRPR in autism has been suggested from studies investigating the role of the X chromosome in autism (consistently with a three times higher prevalence of autism in males than in females) and describing a case of autism linked with an X:8 balanced translocation, where the breakpoint on the X chromosome was located in the first intron of the GRPR gene (Bolton et al. 1995). Similarly, another study described an autistic patient with a duplication of the GRPR locus (Xp22.1–p22.3) (Rao et al. 1994). Recent reports have also proposed a causative role of GRPR dysfunction in CNS disorders because of the altered expression levels of GRP/GRPR in patients with psychiatric, neurodevelopmental, and neurodegenerative disorders, including memory dysfunctions associated with Alzheimer’s disease (AD) (Roesler et al. 2006). Furthermore, increasing evidences of functional interaction between GRPR and other neurotransmitter/receptor signalings (such as dopamine and glucocorticoid receptors) implicated in the pathogenesis of Parkinson’s disease and schizophrenia have also been demonstrated (Roesler et al. 2006). Although a causative role of GRPR in CNS disorders has not been clearly established yet and although there are not many reports on the molecular pathogenesis and on the mechanisms involved in these conditions, it has been suggested that activation of PKC downstream to GRPR with consequent increase in intracellular calcium levels could have a functional role in cooperation with cAMP/PKA pathway during memory formation and memory enhancement in the dorsal hippocampus (Roesler and Schwartsmann 2012) (Fig. 2).
Gastrin-Releasing Peptide Receptor (GRPR), Fig. 2

Molecular mechanisms mediating GRPR signaling in brain function. GRP/BBS binding to GRPR leads to PKC-MAPK activation that potentiates the effect of dopamine receptor on cAMP-PKA to stimulate memory consolidation

Because GRPR signaling has shown functional interactions with other growth factor systems including nerve growth factor (NGF), basic fibroblast growth factor (bFGF/FGF-2), and brain-derived neurotrophic factor (BDNF) that regulate feeding, it has been proposed that BBS/GRP, released from the GI tract in response to food ingestion, could act on CNS to inhibit further food intake, while on the contrary, the suppression of GRP production in the brain could stimulate feeding, therefore creating a bridge between the gut and the brain. All these evidences have led to consider GRPR as a therapeutic target for different neurological and psychiatric conditions where alterations in GRP/GRPR content or signaling have been described (listed in Table 1).
Gastrin-Releasing Peptide Receptor (GRPR), Table 1

GRP/GRPR dysfunction in CNS disorders (Roesler and Schwartsmann 2012)

Alzheimer’s disease

Anxiety disorders


Eating disorders

Parkinson’s disease


Besides CNS disorders, alterations of GRPR signaling have been also described in various inflammatory processes including colonic and gastrointestinal inflammation, arthritis, uveitis, and acute lung inflammation. Moreover, GRP/GRPR expression has been found in lymphocytes, neutrophils, eosinophils, macrophages, and mast cells (Furness et al. 1999), suggesting GRPR as a molecular target for inflammatory disorders, in line with a recent report demonstrating a reduction of proinflammatory cytokines (TNF and IL-1) from activated macrophages in response to specific antagonist of the GRPR (RC-3095) (Dal-Pizzol et al. 2006).

GRPR Expression in Tumors

Growth factor receptors, like GRPR, have been involved in many steps of tumor development and tumor progression, and their over-expression on cancer cells surface is normally associated with a more aggressive behavior. Numerous publications have described high expression of GRPRs in different types of cancer of neuroendocrine (bronchial and gastrointestinal cancer) and non-neuroendocrine origin (squamous, large cell and adenocarcinoma of the lung, colorectal cancer, neuroblastoma, and ovarian and prostate cancer) (Laukkanen and Castellone 2016) (Table 2).
Gastrin-Releasing Peptide Receptor (GRPR), Table 2

GRP/GRPR expressing tumors (Laukkanen and Castellone 2016)






Head and neck








Small cell lung cancer (SCLC) is considered one of the most aggressive and lethal neuroendocrine tumors. High expression of GRP/GRPR has been demonstrated in SCLC where these peptides act as paracrine and autocrine growth factors, essential for cancer development and maintenance (Watkins et al. 2003). A recent study has investigated the molecular signaling mediating GRPR effect in SCLC identifying a cross talk with the sonic hedgehog (Shh) signaling pathway and suggesting that the oncogenic effect of GRP/GRPR on cancer cells could be direct as well as indirect, through activation of other signaling pathways, and could work in an autocrine way as well as in a paracrine manner in promoting cancer growth and progression through interaction with stromal neighboring cells (Castellone et al. 2015) (Fig. 3).
Gastrin-Releasing Peptide Receptor (GRPR), Fig. 3

Molecular mechanisms regulating BBS/GRPR effect in SCLC cells. Binding of BBS/GRP to GRPR induces Gαq and Gα12/Gα13 signaling leading to NFkB transcription factor activation through Rho GTPase. Activation of NFkB increases Shh production that works in an autocrine way, through activation of Smo receptor on SCLC cells, as well as in a paracrine manner, through activation of Shh signaling in neighboring/stromal cells

Several studies have reported aberrant activation of GRP/GRPR signaling in a substantial fraction of colorectal cancer CRC patients (38–76%) and have correlated this positivity to more invasive behavior for the ability of GRPR to regulate morphological and adhesive properties of CRC through interaction with the cyclooxygenase-2 (Cox2) signaling (Gupta and Dubois 2001; Jensen et al. 2001).

GRPR as a Molecular Target

Because GRP/GRPR signaling is involved in a number of human diseases and in several malignancies, the inhibition of this ligand/receptor complex represents an attractive target for therapy. Several inhibitory approaches have been developed in the past years (Reviewed in Laukkanen and Castellone 2016). The most promising are represented by GRPR antagonists (RC-3095 and RC-3940-II) that have demonstrated a strong anticancer effect in vitro and in vivo when used alone or in combination protocols with other chemotherapeutic agents. Alternative approaches are represented by monoclonal antibodies against BLPs (2A11-mAb) that have demonstrated growth inhibition of lung and squamous cell carcinoma of the head and neck and from antisense oligodeoxynucleotides (ODN) directed against GRPR mRNA, able to reduce proliferation of SCLC cells as well as of other GRP responding cells. Finally, the most innovative therapeutic alternative is represented by the development of nanoparticle-mediated delivery of BBS-GRP/GRPR molecules. BBS conjugated to poly(lactic-co-glycolic acid)(PLGA) nanoparticles targeting delivery of docetaxel (DTX) in GRPR overexpressing cells has been recently successfully tested in breast cancer with encouraging results because of its ability to overcame nonspecific toxicity and to reduce the off-target effects of chemotherapy compounds.


GRP/GRPR complex has been shown to play a crucial role during embryonic development and in a number of health disorders, but due to the lack of selective tools, the therapeutic interest concerning this system has been delayed. Only more recently, with the discovery that GRP/GRPRs are frequently expressed in cancer cells, with a limited distribution in normal tissues, more effort has been put toward the identification of inhibitors that would target these peptides/growth factor receptors alone or in combination with conventional chemotherapies. Among these approaches, receptor antagonists, monoclonal antibodies, and antisense oligonucleotides have shown promising results in animal studies as well as in early clinical trials. The growing interest to identify novel small molecules with increased receptor affinity and to test alternative administration methods (using, for instance, metal nanoparticles with a prolonged half-life and a reduced toxicity for healthy tissues) will provide additional strategies to block the autocrine and/or paracrine neuropeptide activation and offer novel therapeutic weapons for all the disorders where GRP/GRPR activation has been demonstrated, like cancer or CNS disorders.

See Also


  1. Bolton P, Powell J, Rutter M, Buckle V, Yates JR, Ishikawa-Brush Y, Monaco AP. Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1). Psychiatr Genet. 1995;5:51–5.PubMedCrossRefGoogle Scholar
  2. Castellone MD, Laukkanen MO, Teramoto H, Bellelli R, Alì G, Fontanini G, Santoro M, Gutkind JS. Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma. Oncogene. 2015 Mar 26;34(13):1679–87.PubMedCrossRefGoogle Scholar
  3. Dal-Pizzol F, Di Leone LP, Ritter C, Martins MR, Reinke A, Pens Gelain D, Zanotto-Filho A, de Souza LF, Andrades M, Barbeiro DF, Bernard EA, Cammarota M, Bevilaqua LR, Soriano FG, Cláudio J, Moreira F, Roesler R, Schwartsmann G. Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis. Am J Respir Crit Care Med. 2006;173:84–90.PubMedCrossRefGoogle Scholar
  4. Furness JB, Kunze WA, Clerc N. The intestine as a sensory organ: neural, endocrine, and immune responses. Am J Phys. 1999;277:922–8.Google Scholar
  5. Ghatei MA, Jung RT, Stevenson JC, Hillyard CJ, Adrian TE, Lee YC, Christofides ND, Sarson DL, Mashiter K, MacIntyre I, Bloom SR. Bombesin: action on gut hormones and calcium in man. J Clin Endocrinol Metab. 1982;54:980–5.PubMedCrossRefGoogle Scholar
  6. Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1:11–21.PubMedCrossRefGoogle Scholar
  7. Helmich MR, Ives KL, Udupi V, et al. Multiple protein kinase pathways are involved in gastrin-releasing peptide receptor-regulated secretion. J Biol Chem. 1999;274:23901–9.CrossRefGoogle Scholar
  8. Jensen RT, Coy DH, Saeed ZA, Heinz-Erian P, Mantey S, Gardner JD. Interaction of bombesin and related peptides with receptors on pancreatic acinar cells. Ann N Y Acad Sci. 1988;547:138–49.PubMedCrossRefGoogle Scholar
  9. Jensen JA, Carroll RE, Benya RV. The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer. Peptides. 2001;22:689–99.PubMedCrossRefGoogle Scholar
  10. Kurose H. Gα12 and Gα13 as key regulatory mediator in signal transduction. Life Sci. 2003;74:155–61.PubMedCrossRefGoogle Scholar
  11. Laukkanen MO, Castellone MD. Gastrin-releasing peptide receptor targeting in cancer treatment: Emerging signaling networks and therapeutic applications. Curr Drug Targets. 2016;17:508–14.PubMedCrossRefGoogle Scholar
  12. Poitras P, Trudel L, Miller P, Gu CM. Regulation of motilin release: studies with ex vivo perfused canine jejunum. Am J Phys. 1997;272:G4–9.Google Scholar
  13. Rao PN, Klinepeter K, Stewart W, Hayworth R, Grubs R, Pettenati MJ. Molecular cytogenetic analysis of a duplication Xp in a male: further delineation of a possible sex influencing region on the X chromosome. Hum Genet. 1994;94:149–53.PubMedCrossRefGoogle Scholar
  14. Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology. 2006;51:350–7.PubMedCrossRefGoogle Scholar
  15. Roesler R, Schwartsmann G. Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target. Front Endocrinol. 2012;3(159).Google Scholar
  16. Severi C, Jensen RT, Erspamer V, D’Arpino L, Coy DH, Torsoli A, Delle Fave G. Different receptors mediate the action of bombesin-related peptides on gastric smooth muscle cells. Am J Phys. 1991;260:G683–90.Google Scholar
  17. Siehler S. Regulation of RhoGEF proteins by G12/13-coupled receptors. Br J Pharmacol. 2009;158:41–9.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle. 2003;2:196–8.PubMedCrossRefGoogle Scholar
  19. Weigert N, Li YY, Lippl F, Coy DH, Classen M, Schusdziarra V. Role of endogenous bombesin-peptides during vagal stimulation of gastric acid secretion in the rat. Neuropeptides. 1996;30:521–7.PubMedCrossRefGoogle Scholar
  20. Zheng R, Iwase A, Shen R, Goodman Jr OB, Sugimoto N, Takuwa Y, Lerner DJ, Nanus DM. Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase. Oncogene. 2006;25:5942–52.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Alessia Parascandolo
    • 1
  • Maria Domenica Castellone
    • 2
  1. 1.IRCCS SDNNaplesItaly
  2. 2.Institute of Experimental Endocrinology and Oncology (IEOS)CNRNaplesItaly