An orphan receptor discovered in 1993 was called bombesin receptor subtype 3 (BRS-3) because of 47-51% amino acid identity with bombesin (Bn) receptors. Its pharmacology is unknown, because no naturally occurring tissues have sufficient receptors to allow studies. ]Bn-(6 -14) bound to both cell lines with high affinity. Neither Bn nor 14 other naturally occurring Bn peptides bound to hBRS-3 with a K d <1000 nM. Twenty-six synthetic peptides that are high affinity agonists or antagonists at other bombesin receptors had an affinity >1000 nM. Guanosine 5-(,␥-imido)triphosphate inhibited binding to both cells due to a change in receptor affinity. These results demonstrate hBRS-3 has a unique pharmacology. It does not interact with high affinity with any known natural agonist or high affinity antagonist of the Bn receptor family, suggesting the natural ligand is either an undiscovered member of the Bn peptide family or an unrelated peptide. The availability of these cell lines and the hBRS-3 ligand should facilitate identification of the natural ligand for BRS-3, its pharmacology, and cell biology. We made two cell lines stably expressing the human BRS-3 (hBRS-3). hBRS-3 was overexpressed in the huRecently, an orphan receptor that is a member of the heptahelical superfamily of receptors was described in both human small cell lung cancer cells (1) and guinea pig uterus (2). Because this orphan receptor had a high degree of homology to mammalian bombesin receptors (i.e. 51-52% for the gastrinreleasing peptide receptor (GRP-R) 1 and 47% for the neuromedin B receptor (NMB-R) (1, 2)), it was named the BRS-3 for bombesin receptor subtype-3 in one study (1). Studies of the distribution of the receptor mRNA show that BRS-3 has a pattern of expression limited to rat secondary spermatocytes (1), guinea pig brain and pregnant uterus (2), and some tumor cell lines (various human small cell and non-small cell lung cancer cell lines (1), the human ductal breast cancer cell line T47D (3), and the human epidermal cancer cell line A431 (3)). However, the natural ligand that interacts with the BRS-3 is unknown, and its pharmacology is largely unknown because of the lack of a radioligand. In addition, little is known about the cellular basis of action of BRS-3 except that it is coupled to phospholipase C when expressed in Xenopus oocytes (1) or when transfected into Balb 3T3 cells (4). The ability to elucidate the pharmacology of the BRS-3 is not only limited by the lack of a radioligand but also by the lack of a cell containing native BRS-3 receptors in sufficient numbers to allow binding studies to identify a possible radioligand.To deal with this latter issue, in the present study we have used two different strategies to produce cell lines stably expressing the human BRS-3 (hBRS-3) receptor whose pharmacology and coupling will probably closely resemble that of the native hBRS-3. Furthermore, we have discovered a unique ligand that is a synthetic analogue of bombesin-(6 -14), which interacts with high affinity with the hBRS-3. With ...
This following article is written for Prof. Abba Kastin’s Festschrift, to add to the tribute to his important role in the advancement of the role of peptides in physiological, as well as pathophysiological processes. There have been many advances during the 35 years of his prominent role in the Peptide field, not only as editor of the journal Peptides, but also as a scientific investigator and editor of two volumes of the Handbook of Biological Active Peptides [146,147]. Similar to the advances with many different peptides, during this 35 year period, there have been much progress made in the understanding of the pharmacology, cell biology and the role of (Bombesin) Bn receptors and their ligands in various disease states, since the original isolation of bombesin from skin of the European frog Bombina bombina in 1970 [76]. This paper will briefly review some of these advances over the time period of Prof Kastin 35 years in the peptide field concentrating on the advances since 2007 when many of the results from earlier studies were summarized [128,129]. It is appropriate to do this because there have been 280 articles published in Peptides during this time on Bombesin-related peptides and it accounts for almost 5% of all publications. Furthermore, 22 Bn publications we have been involved in have been published in either Peptides [14,39,55,58,81,92,93,119,152,216,225,226,231,280,302,309,355,361,362] or in the Prof Kastin’s Handbook of Biological Active Peptides [137,138,331].
The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. The 399-amino acid orphan receptor, bombesin receptor subtype 3 (BRS-3), 1 shares 51 and 47% amino acid sequence homology with the mammalian bombesin (Bn) receptors (gastrinreleasing peptide receptor (GRP-R) and the neuromedin B receptor (NMB-R), respectively) (1, 2). Studies of the distribution of this orphan receptor show that the BRS-3 receptor is present in the central nervous system and peripheral tissues although the distribution is more limited than the GRP-R and NMB-R (3-6). The BRS-3 receptor has been found on such diverse structures as secondary spermatocytes, pregnant uterus, a number of brain regions, and some human lung, breast, and epidermal cancer cell lines (1, 2)The role of BRS-3 in physiological or pathological processes is unknown even though BRS-3-deficient mice, produced by targeted disruption, develop obesity, diabetes, and hypertension (7). These results (7) suggest that the BRS-3 receptor may be required for the regulation of glucose metabolism, energy balance, and maintenance of blood pressure. This proposition is yet to be confirmed because the natural ligand of the BRS-3 receptor is still unknown. Results from previous studies (8 -10) have demonstrated that the hBRS-3 receptor has a unique pharmacology compared with that of any of the closely related Bn receptor family.
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