GRPR

Official Full Name

gastrin releasing peptide receptor

Organism

Homo sapiens

GeneID

2925

Background

Gastrin-releasing peptide (GRP) regulates numerous functions of the gastrointestinal and central nervous systems, including release of gastrointestinal hormones, smooth muscle cell contraction, and epithelial cell proliferation and is a potent mitogen for neoplastic tissues. The effects of GRP are mediated through the gastrin-releasing peptide receptor. This receptor is a glycosylated, 7-transmembrane G-protein coupled receptor that activates the phospholipase C signaling pathway. The receptor is aberrantly expressed in numerous cancers such as those of the lung, colon, and prostate. An individual with autism and multiple exostoses was found to have a balanced translocation between chromosome 8 and a chromosome X breakpoint located within the gastrin-releasing peptide receptor gene. [provided by RefSeq, Jul 2008]

Synonyms

BB2; BB2R; BRS2;

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Detailed Information

Gastrin-releasing peptide (GRP), a 27-amino acid mammalian neuropeptide, is the homolog of the 14-amino acid amidated amphibian peptide bombesin and originally isolated from the skin of the European frog Bombina bombina. GRP acts by binding to the GRP receptor (GRPR, also called BB2), located on cell membranes. Over the past three decades accumulating evidence has suggested that the GRP/GRPR system influences a broad spectrum of physiological processes including thermal regulation, glicemia, feeding, gastrin and somatostatin release, pancreatic secretion, gastric acid secretion, gastrointestinal motility, lung development, pain perception, itch responses, memory formation and expression, cell proliferation, stress responses, and chemoattraction in the immune system.

GRPR Signaling

Experiments using different types of normal and tumor cells from humans and rodents have provided consistent evidence that the GRPR is directly coupled to the Gq type of G protein, and GRPR activation leads to an increase in cellular [Ca²⁺] and stimulation of the phospholipase C (PLC)/protein kinase C (PKC) and extracellular signal-regulated protein kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways. GRPR signaling also interacts with a range of other enzymes (e.g., phospholipases A2 and D, tyrosine kinases, ciclooxigenase-2, and phosphatidylinositol 3-kinase (PI3K)), growth factor receptor systems (including epidermal growth factor receptor, EGFR, and TrkB), and immediate-early genes. When GRP activates GRPR, inactive guanosine diphosphate (GDP)–bound G protein is activated to guanosine triphosphate (GTP)–bound state, resulting in metalloprotease-dependent increased release of EGFR pro-ligands, subsequent phosphorylation of EGFR, and activation of RAS/RAF/ MAPK downstream pathway (Figure 1).

Figure 1. GRP/GRPR signaling pathway.

GRPR regulation of emotional memory and stress

The role of GRPR in memory formation and expression has been examined by pharmacological and genetic studies in rodents. Early experiments reported by Flood and Morley showed that systemic or intracerebroventricular (i.c.v.) delivery of GRP or bombesin after behavioral training could modulate the retention for a T-maze footshock avoidance task. Subsequent studies found memory-enhancing effects of systemic, intra-NTS or intrahippocampal posttraining administration of bombesin in rats. The evidence for a modulatory role of the GRPR on memory formation was further extended by experiments using selective antagonists.

The GRPR might play a crucial role in both stress and the formation of emotionally-motivated memory, and might be a crucial component of a pathway that integrates fear memory consolidation and responses to stress hormones. This is consistent with the involvement of abnormal GRPR signaling in neurological and psychiatric disorders involving cognitive dysfunction and anxiety. The findings from a few human studies support this possibility, showing, for example, changes in GRP levels in samples from patients with schizophrenia or suicides, as well as altered GRPR-triggered cellular responses in patients with Alzheimer’s disease (AD).

GRPR and cancer

GRPR overexpression in prostate tumors has been identified at both the mRNA level and the protein level in radical prostatectomy specimens. Using receptor autoradiography, Markwalder and Reubi found that primary prostatic carcinomas often express GRPR at much higher levels than non-neoplastic prostate glands. Although peptide receptor targeting is normally based on overexpression of receptors in tumor cells, some genitourinary tumors have been found to overexpress GRPR in tumoral and peritumoral vessels. In one study, GRPR was expressed in the tumoral blood vessels of 92% of patients with urinary tract cancers, but not in the neoplastic tumor cells of any patient. The GRPR is also expressed in the neoplastic cells of renal cell carcinoma, lung cancer, breast cancer, colon cancer, gastrinoma, endometrial cancer and gastrointestinal stromal tumors. Other cancers, such as ovarian and pancreatic cancers, express GRPR in their tumoral vessels. Ovarian cancers express GRPR in the blood vessels of not only the primary tumor but also of metastases and the receptors are at a higher density in these distant sites.

A number of human cancers have been evaluated for expression of vascular GRPR and the vascular endothelial growth factor receptor (VEGFR), the latter being an established biological marker of angiogenesis. All GRPR-positive vessels concomitantly expressed the VEGFR, which suggests that GRPR might be a target for antiangiogenic tumor therapy. In the evolving field of antiangiogenic therapies that aim to destroy tumor vessels, such GRPR-expressing vessels might be attractive targets. A GRPR-based antiangiogenic therapy would be useful in the palliative setting, where the current therapeutic options comprise cisplatin-based combination chemotherapy and second-line vinflunine.

References:

Mattei J, et al. Gastrin-Releasing Peptide Receptor Expression in Lung Cancer. Archives of Pathology & Laboratory Medicine, 2014, 138(1):98-104.
Roesler R, et al. Gastrin-releasing peptide receptor signaling in the integration of stress and memory. Neurobiology of Learning & Memory, 2014, 112:44-52.
Roesler R, Schwartsmann G. Gastrin-releasing peptide receptors in the central nervous system: Role in brain function and as a drug target. Frontiers in Endocrinology, 2012, 3:159.
Mansi R, et al. Targeting GRPR in urological cancers - From basic research to clinical application. Nature Reviews Urology, 2013, 10(4).

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