Alternative titles; symbols
HGNC Approved Gene Symbol: GRP
Cytogenetic location: 18q21.32 Genomic coordinates (GRCh38): 18:59,219,189-59,230,771 (from NCBI)
Gastrin-releasing polypeptide is the mammalian equivalent of the amphibian tetradecapeptide bombesin. In nanogram amounts, both GRP and bombesin infused into humans increase plasma gastrin (137250), pancreatic polypeptide (167780), glucagon (138030), gastric inhibitory peptide, and insulin (176730). Bombesin is also a potent neuroregulator. Bombesin-like immunoreactivity has a high level in neuroendocrine cells of the lung. High levels are found in the human lung just after birth and levels decrease thereafter in parallel with the observed disease in number of pulmonary neuroendocrine cells. Bombesin immunoreactivity is high in pulmonary carcinoid tumors and in some small cell carcinomas of the lung (182280).
Spindel et al. (1984) used RNA from a lung carcinoid tumor to prepare cDNA encoding GRP. They showed that the GRP gene codes for a precursor of 148 amino acids. GRP is a 27-amino acid neuropeptide.
Spindel et al. (1986) found 2 alternative mRNAs read from 1 gene by a frameshift. The sequence of the 2 product peptides differed by 27 amino acids. By comparison of the sequence of cDNA with that of a genomic prepro-GRP clone, Sausville et al. (1986) found 3 forms of mRNA arising from a single primary transcript which undergoes alternative processing from 2 splice donor sites to 2 splice acceptor sites.
Shumyatsky et al. (2002) showed that mouse Grp is highly expressed both in the lateral nucleus of the amygdala, the nucleus where associations for pavlovian learned fear are formed, and in the regions that convey fearful auditory information to the lateral nucleus. Moreover, they found that Grp receptor (GRPR; 305670) is expressed in GABAergic interneurons of the lateral nucleus. Grp excited these interneurons and increased their inhibition of principal neurons. Grpr-deficient mice showed decreased inhibition of principal neurons by the interneurons, enhanced long-term potentiation (LTP), and greater and more persistent long-term fear memory. In contrast, these mice performed normally in hippocampus-dependent Morris maze. These experiments provided genetic evidence that GRP and its neural circuitry operate as a negative feedback regulating fear and established a causal relationship between GRPR gene expression, LTP, and amygdala-dependent memory for fear.
Kanashiro et al. (2003) found that the proliferation of the DMS-153 small cell lung carcinoma cell line in vitro was stimulated by GRP and IGF2 (147470) and inhibited by a GHRH (139190) antagonist. The cell line expressed mRNAs for GHRH and GHRH receptor (GHRHR; 139191) splice variants 1 and 2, suggesting that GHRH is an autocrine growth factor. Kanashiro et al. (2003) examined the effects of GHRH and GRP antagonists on tumors produced by DMS-153 cells xenografted into nude mice. Treatment with a GHRH antagonist reduced tumor volume by 28%, while a GRP antagonist reduced tumor volume by 77%. A combination of both antagonists reduced tumor volume by 95%. Western blot analysis indicated that the antitumor effects were associated with reduced expression of TP53 (191170) containing a tumor-associated mutation. Serum Igf1 (147440) levels were diminished in animals receiving GHRH antagonists, and the mRNA levels of Igf2, Igf receptor-1 (147370), Grpr, and Egf receptor (131550) were reduced following the combined treatment.
Sun and Chen (2007) found that GRP is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, whereas expression of its receptor GRPR is restricted to lamina I of the dorsal spinal cord. Grpr mutant mice showed comparable thermal, mechanical, inflammatory, and neuropathic pain responses relative to wildtype mice. In contrast, induction of scratching behavior was significantly reduced in Grpr mutant mice in response to pruritogenic stimuli. Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behavior in 3 independent itch models. Sun and Chen (2007) concluded that their data demonstrated that GRPR is required for mediating the itch sensation rather than pain at the spinal level.
Li et al. (2016) used molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in the murine brain. Small neural subpopulations in a key breathing control center, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), express neuromedin B (NMB; 162340) or GRP. These project to the preBotzinger complex (pre-BotC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of about 200 neurons. Introducing either neuropeptide into preBotC or onto preBotC slices induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing but left breathing otherwise intact initially. Li et al. (2016) proposed that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiologic and perhaps emotional input to transform normal breaths into sighs.
In human-mouse somatic cell hybrids, Naylor et al. (1985, 1987) found that a GRP probe segregated with chromosome 18 and the marker peptidase A. By in situ hybridization, the localization was narrowed to 18q21 (Lebacq-Verheyden et al., 1987). Using molecular probes in the analysis of an interspecific backcross between C57BL/6J and Mus spretus, Justice et al. (1992) mapped the corresponding gene to mouse chromosome 18.
Justice, M. J., Gilbert, D. J., Kinzler, K. W., Vogelstein, B., Buchberg, A. M., Ceci, J. D., Matsuda, Y., Chapman, V. M., Patriotis, C., Makris, A., Tsichlis, P. N., Jenkins, N. A., Copeland, N. G. A molecular genetic linkage map of mouse chromosome 18 reveals extensive linkage conservation with human chromosomes 5 and 18. Genomics 13: 1281-1288, 1992. [PubMed: 1354644] [Full Text: https://doi.org/10.1016/0888-7543(92)90047-v]
Kanashiro, C. A., Schally, A. V., Groot, K., Armatis, P., Bernardino, A. L. F., Varga, J. L. Inhibition of mutant p53 expression and growth of DMS-153 small cell lung carcinoma by antagonists of growth hormone-releasing hormone and bombesin. Proc. Nat. Acad. Sci. 100: 15836-15841, 2003. [PubMed: 14660794] [Full Text: https://doi.org/10.1073/pnas.2536558100]
Lebacq-Verheyden, A.-M., Bertness, V., Kirsch, I., Hollis, G. F., McBride, O. W., Battey, J. Human gastrin-releasing peptide gene maps to chromosome band 18q21. Somat. Cell Molec. Genet. 13: 81-86, 1987. [PubMed: 3027901] [Full Text: https://doi.org/10.1007/BF02422302]
Li, P., Janczewski, W. A., Yackle, K., Kam, K., Pagliardini, S., Krasnow, M. A., Feldman, J. L. The peptidergic control circuit for sighing. Nature 530: 293-297, 2016. [PubMed: 26855425] [Full Text: https://doi.org/10.1038/nature16964]
Naylor, S. L., Sakaguchi, A. Y., Spindel, E., Chin, W. W. Human gastrin-releasing peptide gene is located on chromosome 18. Somat. Cell Molec. Genet. 13: 87-91, 1987. [PubMed: 3027902] [Full Text: https://doi.org/10.1007/BF02422303]
Naylor, S. L., Spindel, E., Chin, W. W., Sakaguchi, A. Y. Gastrin releasing peptide gene is located on human chromosome 18. (Abstract) Cytogenet. Cell Genet. 40: 711 only, 1985.
Sausville, E. A., Lebacq-Verheyden, A.-M., Spindel, E. R., Cuttitta, F., Gazdar, A. F., Battey, J. F. Expression of the gastrin-releasing peptide gene in human small cell lung cancer: evidence for alternative processing resulting in three distinct mRNAs. J. Biol. Chem. 261: 2451-2457, 1986. [PubMed: 3003116]
Shumyatsky, G. P., Tsvetkov, E., Malleret, G., Vronskaya, S., Hatton, M., Hampton, L., Battey, J. F., Dulac, C., Kandel, E. R., Bolshakov, V. Y. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111: 905-918, 2002. [PubMed: 12526815] [Full Text: https://doi.org/10.1016/s0092-8674(02)01116-9]
Spindel, E. R., Chin, W. W., Price, J., Rees, L. H., Besser, G. M., Habener, J. F. Cloning and characterization of cDNAs encoding human gastrin-releasing peptide. Proc. Nat. Acad. Sci. 81: 5699-5703, 1984. [PubMed: 6207529] [Full Text: https://doi.org/10.1073/pnas.81.18.5699]
Spindel, E. R., Zilberberg, M. D., Habener, J. F., Chin, W. W. Two prohormones for gastrin-releasing peptide are encoded by two mRNAs differing by 19 nucleotides. Proc. Nat. Acad. Sci. 83: 19-23, 1986. [PubMed: 3001723] [Full Text: https://doi.org/10.1073/pnas.83.1.19]
Sun, Y.-G., Chen, Z.-F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448: 700-703, 2007. [PubMed: 17653196] [Full Text: https://doi.org/10.1038/nature06029]