HGNC Approved Gene Symbol: GRPR
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38): X:16,123,565-16,153,518 (from NCBI)
Expression of gastrin-releasing polypeptide (GRP; 137260) and its receptor in tumors suggests that these molecules are part of an autocrine loop for growth. Spindel et al. (1990) cloned the human GRP receptor cDNA from a library made from a small cell lung carcinoma cell line using the mouse GRP receptor. The cDNA was in turn used to screen a human genomic library.
Corjay et al. (1991) cloned GRPR from NCI-H345 human lung carcinoma cells. The deduced 384-amino acid protein has 7 predicted transmembrane domains characteristic of a G protein-coupled receptor. GRPR and NMBR (162341) share 55% amino acid identity, with highest conservation in transmembrane domain-3. Both proteins have consensus protein kinase C (see 176960) phosphorylation sites in a cytoplasmic loop and a C-terminal domain. GRPR and NMBR also share a similar gene structure, suggesting that they evolved from a common ancestor. Human GRPR shares 90% identity with rodent Grpr.
By in situ hybridization of rat brain, Wada et al. (1991) detected Grpr expression in suprachiasmatic nucleus, paraventricular nucleus, lateral olfactory tract nucleus, magnocellular preoptic nucleus, and lateral mammillary nucleus. Weaker expression was detected in other brain regions. Wada et al. (1991) noted that this pattern of expression in brain differed from that found for Nmbr.
Corjay et al. (1991) showed that expression of GRPR in Xenopus oocytes induced a depolarizing response following application of GRP. The response was blocked by a GRPR antagonist.
Activation of GRPR in human airways has been associated with the proliferative response of bronchial cells to GRP and with long-term tobacco use. Increasing evidence demonstrates that women are more susceptible than men to tobacco carcinogenesis. Shriver et al. (2000) hypothesized that the susceptibility of women to the effects of tobacco may be associated with airway expression of GRPR. Shriver et al. (2000) analyzed GRPR mRNA expression in lung tissues and cultured airway cells from 78 individuals (40 males and 38 females) and in lung fibroblasts exposed to nicotine in vitro. Shriver et al. (2000) detected GRPR mRNA expression in airway cells and tissues of more female than male nonsmokers (55% vs 0%) and short-term smokers with a 1 to 25 pack-year history (75% vs 20%), 'pack-years' being defined as the number of packs of cigarettes smoked per day multiplied by the number of years of smoking. Female smokers exhibited expression of GRPR mRNA at a lower mean pack-year exposure than male smokers. Lung fibroblasts and bronchial epithelial cells exhibited high-affinity, saturable nicotinic acetylcholine-binding sites. Expression of GRPR mRNA in lung fibroblasts was elevated following exposure to nicotine. Shriver et al. (2000) suggested that the presence of 2 expressed copies of the GRPR gene in females may be a factor in the increased susceptibility of women to tobacco-induced lung cancer.
Sun et al. (2009) selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine dependence. In contrast, pain behaviors were unaffected. Sun et al. (2009) concluded that their data suggested that GRPR-positive neurons are different from the spinothalamic tract neurons that have been the focus of the debate regarding whether there are separate neuronal pathways for itch and pain. Sun et al. (2009) suggested that the GRPR+ neurons constitute a long-sought labeled line for itch sensation in the spinal cord.
Yu et al. (2017) found that mice scratched after observing a conspecific scratching. Molecular mapping showed increased neuronal activity in the suprachiasmatic nucleus (SCN) of the hypothalamus of mice that displayed contagious scratching. Ablation of GRPR or GRPR neurons in the SCN abolished contagious scratching behavior, which was recapitulated by chemogenetic inhibition of SCN GRP (137260) neurons. Activation of SCN GRP/GRPR neurons evoked scratching behavior. Yu et al. (2017) concluded that these data demonstrated that GRP-GRPR signaling is necessary and sufficient for transmitting contagious itch information in the SCN.
Corjay et al. (1991) determined that the GRPR gene contains 3 exons.
Schantz et al. (1991) designed PCR primers that span the exon encoding amino acids 139 to 256 of the GRP receptor and used these for the analysis of somatic cell hybrids. In this way they found that the GRPR gene is located on the X chromosome. A panel of hybrids with translocations of the X chromosome permitted regionalization of the gene to Xp11-q11. Maslen and Boyd (1993) found that GRPR maps to Xp22.3-p21.2 rather than to the Xp11-q11 interval as previously reported. The assignment of GRPR to distal Xp was supported by the comparative map position in the mouse. The mapping in the human was done by means of PCR amplification from a panel of somatic cell hybrids that retained reduced portions of the X chromosome; the mapping in the mouse was done by linkage studies in interspecific backcross matings.
Shiraishi et al. (1996) noted that within the haploid genome there are approximately 1,000 copies of the human endogenous retrovirus-like sequence, HERV-H. Although these sequences are scattered throughout the genome, in situ hybridization experiments showed discrete clusters positioned on 1p and 7q. Shiraishi et al. (1996) located 3 HERV-H sequences that were unexpectedly clustered within a 300-kb region close to the GRPR locus on the X chromosome.
Ishikawa-Brush et al. (1997) reported molecular studies of a 27-year-old female patient with a balanced translocation 46,X,t(X;8)(p22.13;q22.1) and associated with multiple exostoses and autism (209850; Bolton et al., 1995). Multiple exostoses were present around the ankles, knees, wrists, and left clavicle, and the patient had short stature, short span, and small hands with short fourth and fifth metacarpals. She had mild brachycephaly and was diagnosed as autistic according to the International Classification of Diseases Criteria. She was mentally retarded with an IQ of 35 and also suffered from grand mal epilepsy. The translocated X chromosome was demonstrated to be active by bromodeoxyuridine analysis. The father was deceased; the mother and a brother were known to have normal karyotypes and no clinical signs of multiple exostoses or autism. Through molecular analysis using YAC and cosmid clones, Ishikawa-Brush et al. (1997) isolated the translocation breakpoint and confirmed that it was reciprocal between a 5-prime-GGCA-3-prime sequence found on both chromosomes X and 8, without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of GRPR and that on chromosome 8 occurred approximately 30 kb distal to the 3-prime end of the syndecan-2 gene (SDC2; 142460). The orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. The authors speculated that a dosage effect of the GRPR gene and a position effect of the SDC2 gene may have contributed to the phenotype in this patient. They demonstrated that the GRPR gene escapes X inactivation; nevertheless, the gene from the inactive X chromosome may be expressed at only a fraction of the active allele. Such a low dosage might have been sufficient to cause autism in this patient. It is unknown, furthermore, whether inactivation patterns for a given gene are consistent throughout every tissue and cell within the body. This does not appear to be true for imprinted genes, so it is possible that GRPR could escape inactivation in test tissues, such as fibroblasts and lymphoblasts (and other tissues), but could be subject to inactivation in the brain, resulting in no GRPR expression and the observed phenotype. Therefore, Ishikawa-Brush et al. (1997) suggested that examination for rearrangements and point mutations in the GRPR gene and association studies using polymorphisms within and flanking the gene are clearly warranted in patients with autism. The SDC2 gene product is a member of a family of cell surface heparan sulfate proteoglycans that interact with adhesion molecules, growth factors, and a variety of other effectors that support the shaping, maintenance, and repair of an organism. One of its biologic functions is related to aggregating cells in the formation of bone and therefore is consistent with a possible role in multiple exostoses. However, the gene was not disrupted by the translocation breakpoint in this patient and alteration in its expression was not demonstrated. Since translocations occurring as much as 100 kb from the 3-prime end of the PAX6 gene (607108) can be disruptive to the gene through position effect, the translocation reported by Ishikawa-Brush et al. (1997) might be another example of this phenomenon in relation to SDC2 or other genes in 8q22.1.
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 Grpr 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.
Sun and Chen (2007) found that GRPR plays an important role in mediating itch sensation in the dorsal spinal cord. The authors found that gastrin-releasing peptide (GRP; 137260) 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.
Bolton, P., Powell, J., Rutter, M., Buckle, V., Yates, J. R. W., Ishikawa-Brush, Y., Monaco, A. P. Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1). Psychiat. Genet. 5: 51-55, 1995. [PubMed: 7551962] [Full Text: https://doi.org/10.1097/00041444-199522000-00001]
Corjay, M. H., Dobrzanski, D. J., Way, J. M., Viallet, J., Shapira, H., Worland, P., Sausville, E. A., Battey, J. F. Two distinct bombesin receptor subtypes are expressed and functional in human lung carcinoma cells. J. Biol. Chem. 266: 18771-18779, 1991. [PubMed: 1655761]
Ishikawa-Brush, Y., Powell, J. F., Bolton, P., Miller, A. P., Francis, F., Willard, H. F., Lehrach, H., Monaco, A. P. Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3-prime to the SDC2 gene. Hum. Molec. Genet. 6: 1241-1250, 1997. [PubMed: 9259269] [Full Text: https://doi.org/10.1093/hmg/6.8.1241]
Maslen, G. L., Boyd, Y. Comparative mapping of the Grpr locus on the X chromosomes of man and mouse. Genomics 17: 106-109, 1993. [PubMed: 8406441] [Full Text: https://doi.org/10.1006/geno.1993.1290]
Schantz, L. J., Naylor, S. L., Giladi, E., Spindel, E. R. Assignment of the GRP receptor gene to the human X chromosome. (Abstract) Cytogenet. Cell Genet. 58: 2085-2086, 1991.
Shiraishi, M., Alitalo, T., Sekiya, T. The chromosomal organization of the human endogenous retrovirus-like sequence HERV-H: clustering of the HERV-H sequences in a 300-kb region close to the GRPR locus on the X chromosome. DNA Res. 3: 425-429, 1996. [PubMed: 9097046] [Full Text: https://doi.org/10.1093/dnares/3.6.425]
Shriver, S. P., Bourdeau, H. A., Gubish, C. T., Tirpak, D. L., Davis, A. L. G., Luketich, J. D., Siegfried, J. M. Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J. Nat. Cancer Inst. 92: 24-33, 2000. [PubMed: 10620630] [Full Text: https://doi.org/10.1093/jnci/92.1.24]
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., Giladi, E., Brehm, P., Goodman, R. H., Segerson, T. P. Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Molec. Endocr. 4: 1956-1963, 1990. [PubMed: 1707129] [Full Text: https://doi.org/10.1210/mend-4-12-1956]
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]
Sun, Y.-G., Zhao, Z.-Q., Meng, X.-L., Yin, J., Liu, X.-Y., Chen, Z.-F. Cellular basis of itch sensation. Science 325: 1531-1534, 2009. [PubMed: 19661382] [Full Text: https://doi.org/10.1126/science.1174868]
Wada, E., Way, J., Shapira, H., Kusano, K., Lebacq-Verheyden, A. M., Coy, D., Jensen, R., Battey, J. cDNA cloning, characterization, and brain region-specific expression of a neuromedin-B-preferring bombesin receptor. Neuron 6: 421-430, 1991. [PubMed: 1848080] [Full Text: https://doi.org/10.1016/0896-6273(91)90250-4]
Yu, Y.-Q., Barry, D. M., Hao, Y., Liu, X.-T., Chen, Z.-F. Molecular and neural basis of contagious itch behavior in mice. Science 355: 1072-1076, 2017. [PubMed: 28280205] [Full Text: https://doi.org/10.1126/science.aak9748]