The human GRP-R gene has 3 exons and is localized to chromosome Xp22.2.

The gene has 3 exons. The GRP-R gene spans 30218 bases.

The GRP-R gene has 9 and 3.1 kb transcripts in human stomach as well as NCI-H345 lung cancer cells, T47D breast cancer cells and HuTu 80 duodenal carcinoma cells. The pancreas has 9, 4.6, 3.1 and 2.1 kb transcripts. Polymorphisms are observed at 794 (G-A), 851 (C-T) and 1061 (C-T) but these do not alter the GRP-R sequence (Xiao et al., 2001). The GRP-R gene has 1155 bp.

Bombesin, a 14 amino acid peptide (Anastasi et al., 1974) and gastrin-releasing peptide (GRP), a 27 amino acid peptide (McDonald et al., 1979), bind with high affinity to receptors initially characterized in the rat brain (Moody et al., 1978) and guinea pig pancreatic acini (Jensen et al., 1978). The GRP-R was cloned (Battey et al., 1991; Spindel et al., 1990) and found to be a G-protein coupled receptor (GPCR) containing 384 amino acids. The human GRP-R gene is localized to the X chromosome and the GRP-R has 7 transmembrane (TM ) domains, an extracellular N-terminal and intracellular C-terminal. Exon 1 codes for TM 1, 2 and 3 domains with splice site in IC loop 2 (Asp¹³⁷). Exon 2 codes for TM 4 and 5 with a Gln²⁵⁵ splice site. Exon 3 codes for TM 6-7 domains and the cytoplasmic C-terminal. Exon 1, 2 and 3 have 413 bp, 352 bp and 390 bp respectively whereas introns 1 and 2 are 23 kb and 1.6 kb respectively (Xiao et al., 2001).
The human GRP-R is glycosylated at Asn²⁰, palmitoylated at Cys³³⁹ and has a disulfide between Cys¹¹³ and Cys¹⁹⁶ (Jensen et al., 2008). For GRP-R agonist binding Gln¹²⁰, Pro¹⁹⁸, Arg²⁸⁷ and Ala³⁰⁷ are essential (Akeson et al., 1997). For GRP-R antagonist binding Thr²⁹⁶, Phe³⁰¹ and Ser³⁰⁴ are essential (Tokita et al., 2001). GRP-R antagonists include (Psi^13,14,Leu¹⁴)BB, (D-Phe⁶)BB^6-13propylamide and PD176,252 (Gonzalez et al., 2009).

The GRP-R interacts with Gq causing phosphatidylinositol turnover (Rozengurt, 1998). As a result, BB addition to small cell lung cancer (SCLC) cells causes increased protein kinase C activity and elevation of cytosolic Ca²⁺ (Moody et al., 1987). Also, BB causes tyrosine phosphorylation of EGFR, ERK, FAK, paxillin, and Src leading to increased cellular proliferation (Jensen et al., 2008).

The GRP-R is localized to the normal brain especially the periventricular nucleus (PVN) of the hypothalamus (Wolf et al., 1983) where activation by BB causes satiety (Gibbs et al., 1979). The GRP-R, which regulates insulin secretion, is present in the pancreatic islets (Persson et al., 2002). The GRP-R is present in colonic villi and may play a role in villi development (Carroll et al., 2002). The GRP-R is present on small cell lung cancer (SCLC) cells and BB stimulates whereas Psi^13,14, Leu¹⁴)BB or PD176252 inhibits cellular proliferation (Mahmoud et al., 1991; Moody et al., 2003). The GRP-R is present on squamous cell carcinoma of the head and neck cancer cells and PD176252 inhibits the growth of these cells (Zhang et al., 2007). In colon cancer the transcription factor CREB is a regulator of GRP-R expression (Chinnappan et al., 2008).

The GRP-R is localized to the plasma membrane of normal and cancer cells.

Other receptors of the BB family include neuromedin B (NMB) which contains 390 amino acids (Wada et al., 1991) and has 55% sequence homology with the GRP-R. An orphan receptor named BB receptor subtype 3 (BRS-3) was cloned which contains 399 amino acids and has 51% sequence homology with the GRP-R (Fathi et al., 1993). The GRP receptor binds BB and GRP with high affinity whereas the NMB receptor binds NMB with high affinity. BRS-3 does not bind BB, GRP or NMB with high affinity (Jensen et al., 2008).

The GRP-R gene has 4 point mutations in biopsy specimens from patients with autism spectrum disorders, 2 of which result in amino acid changes (C6S and L181F). The mutated GRP-R had normal agonist binding and second messenger production (Seidita et al., 2008). Also an X-8 translocation occurs in intron 1 of the GRP-R gene in a patient with infantile autism (Ishikawa-Brush et al., 1997).