Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target

Abstract

Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR) superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP) is a mammalian neuropeptide that binds to the GRP receptor (GRPR, BB2). Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS) plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior. In addition, some alterations in GRP or GRPR expression or function have been described in patients with neurodegenerative, neurodevelopmental, and psychiatric disorders, as well as in brain tumors. Findings from preclinical models are consistent with the view that the GRPR might play a role in brain disorders, and raise the possibility that GRPR agonists might ameliorate cognitive and social deficits associated with neurological diseases, while antagonists may reduce anxiety and inhibit the growth of some types of brain cancer. Further preclinical and translational studies evaluating the potential therapeutic effects of GRPR ligands are warranted.

Keywords: bombesin receptors; brain disorders; gastrin-releasing peptide; gastrin-releasing peptide receptor; neuropeptide signaling.

FIGURE 1

Proposed molecular mechanisms mediating GRPR regulation of brain function. The stimulation of hippocampal memory consolidation by GRPR activation depends on PKC, MAPK, PKA, and PI3K, and is potentiated by activation of the D1R/cAMP/PKA pathway (Roesler et al., 2006a, 2009, 2012). GRPR activation at the postsynaptic membrane is coupled to G_q protein activity and increases in [Ca²⁺], leading to stimulation of the PLC/PKC and ERK/MAPK pathways. D1R is coupled to the G_s protein and adenylyl cyclase (AC) activation. The D1R-induced cAMP signal might be potentiated by [Ca²⁺]-induced stimulation of [Ca²⁺]-responsive types of AC (Wong et al., 1999; Chan and Wong, 2005; Roesler et al., 2006b, 2012), providing a possible mechanism for the requirement of cAMP/PKA signaling for GRPR influences on memory. Modified from Roesler et al. (2006b), , with permission.

FIGURE 2

The GRPR agonist bombesin prevents memory impairment induced by beta-amyloid peptide in the rat hippocampus. Data are mean ± SEM retention test step-down latencies (s), in an inhibitory avoidance conditioning, of rats given a bilateral infusion of the GRPR agonist bombesin (BB; 0.002 μg) or saline (SAL; control group) 10 min before being trained in IA, and beta-amyloid peptide (Abeta; 25–35) or distilled water (DW; controls) immediately after IA training. The number of animals was 8–14 per group. **P < 0.01 compared to the control group treated with SAL and DW. Reproduced from Roesler et al. (2006b), with permission.

FIGURE 3

GRPR blockade during CNS development in rats results in long-lasting behavioral alterations associated with experimental models of autistic spectrum disorders (ASDs). Rats were given intraperitoneal injections of saline (SAL; control group) or the GRPR antagonist RC-3095 (1 or 10 mg/kg) twice daily from postnatal days (PN) 1 to 10. A social behavior test was carried out at PN 30. (A) Representative photographs of rats given SAL or RC-3095 (1 or 10 mg/kg) during the social interaction test. (B) Mean ± SEM number of social contacts. (C) Mean ± SEM time spent engaged in social interaction (in seconds). The number of animals was 6–7 per group; **P < 0.01 compared to the control group. Reproduced from Presti-Torres et al. (2007), with permission.

FIGURE 4

GRPR content in human normal brain tissue and brain tumors. Representative sections of (A) normal brain and (B) astrocytoma grade IV from an immunohistochemical study of GRPR content from samples of patients with gliomas and normal brain samples. GRPR staining is shown in the right column (brown, ×400) and hematoxylin–eosin (HE) in the left column (×400). GRPR staining in the normal brain tissue is restricted to neuronal bodies and dendrites, whereas its presence in astrocytoma samples is widespread. Sections were incubated with anti-GRPR antibody, sequentially treated with biotinylated anti-rabbit IgG and streptavidin-biotin peroxidase solution, and then developed with diaminobenzidine as chromogen. Modified from Flores et al. (2010), with permission.

FIGURE 5

A GRPR antagonist inhibits the growth of experimental brain tumors. Rats implanted with C6 experimental gliomas in the striatum were treated for seven consecutive days with intraperitoneal injections of the GRPR antagonist RC-3095 alone (0.1, 0.3, and 1.0 mg/kg twice a day), temozolomide (TMZ) alone (5 mg/kg once a day), or RC-3095 combined with TMZ. Control animals were injected with vehicle. Pharmacological treatments were initiated 10 days after tumor implantation. The number of animals was 6 rats per group. Tumor size was measured 20 days after tumor implantation. Data are shown as median (interquartile ranges) tumor volume (mm³). Values for individual animals are shown by dots; *P < 0.002 compared to control animals. Reproduced from de Oliveira et al. (2009), with permission.