Insights into bombesin receptors and ligands: Highlighting recent advances

Abstract

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].

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

“…Transactivation requires phospholipase-C, not adenylate-cyclase, but stimulation of matrix-melloproteinases, Src-kinases, TGF-alpha release and generation of oxygen-free-radicals[55]. With other GPCR's(bombesin, neurotensin)[95••, 96••, 97] inducing growth in lung-cancer-cells, the simultaneous inhibition of the GPCR by an antagonist and a tyrosine-kinase-inhibitor(gefitinib, etc) leads to potentiated growth-inhibitory effects. These findings raise the possibility that a similar stragey could be consider with VIP/PACAP-receptors on these tumor-cells.…”

Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor

“…The bombesin receptor subtype 3 (BB 3 receptor) is an orphan G-protein-coupled receptor (GPCR) classified as a member of the mammalian bombesin receptor (BnR) family, because of its high homology to the known mammalian BnR members [gastrin-releasing peptide receptor (BB 2 receptor) and the neuromedin B receptor (BB 1 receptor)] [1–3]. However, there is little known of BB 3 receptor’s roles in physiological or pathological processes [2–5].…”

“…However, there is little known of BB 3 receptor’s roles in physiological or pathological processes [2–5]. This has occurred because its native ligand is unknown, it has low affinity for all natural Bn peptides, and unlike BB 2 or BB 1 receptor, for which numerous selective agonists and antagonists are described [2,6–11], until recently no agonist or antagonist with sufficient selectivity to be useful for in vivo studies, existed for BB 3 receptor [2,3,12–17]. A high affinity BB 3 receptor agonist has been described, [D-Tyr 6 , β-Ala 11 , Phe 13 , Nle 14 ]Bn(6–14) (peptide #1), which allowed studies of BB 3 receptor’s signaling cascades, demonstrating it was coupled to phospholipase C, A2 and D activation as well as tyrosine kinase cascades [4,14,18–21].…”

“…At present, some insights into the possible importance of BB 3 receptor either physiologically or in pathological conditions have come from studies of mice in which BB 3 receptor has been removed by targeted deletion (BB 3 receptor -KO mice) [3,13,29–33]. These studies and others provide evidence that, similar to the other BnRs (i.e.…”

“…These studies and others provide evidence that, similar to the other BnRs (i.e. BB 2 receptor /BB 1 receptor), BB 3 receptor is important in regulation of feeding/satiety[34] in addition to regulation of various behaviors, glucose and insulin homeostasis, as well as metabolic homeostasis, and may play an important role in diabetes and obesity [3,13,15,29,30,32,33]. However, BB 3 receptor selective antagonists/agonists would be invaluable to further investigate BB 3 receptor role in these and other areas.…”