Bombesin receptor subtype 3 as a potential target for obesity and diabetes

Abstract

Summary Introduction Diabetes mellitus and obesity are important health issues; increasing in prevalence, both in the US and globally. There are only limited pharmacological treatments, and although bariatric surgery is effective, new effective pharmacologic treatments would be of great value. This review covers one area of increasing interest that could yield new novel treatments of obesity/diabetes mellitus. It involves recognition of the central role the G-protein-coupled receptor, bombesin receptor subtype 3(BRS-3) plays in energy/glucose metabolism. Areas covered Since the initial observation that BRS-3-knockout mice develop obesity, hypertension, impaired glucose-metabolism, and hyperphagia, there has been numerous studies of the mechanisms involved and the development of selective BRS-3-agonists/ antagonists which have marked effects on body weight, feeding, and glucose/insulin homeostasis. In this review each of these areas will be briefly reviewed. Expert opinion BRS-3 plays an important role in glucose/energy homeostasis. The development of potent, selective BRS-3 agonists demonstrates promise as a novel approach to treat obesity/diabetic states. One important question that needs to be addressed is whether BRS-3 agonists need to be centrally-acting. This is particular important in light of recent animal and human studies that report transient cardiovascular side-effects with centrally acting oral BRS-agonists.

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

“…In the present study, we found that peptide antagonist Bantag-1 had a high affinity for BB 3 receptor as reported previously [14,15] and high selectivity for BB 3 receptor, with a >30,000-fold higher affinity for BB 3 receptor over BB 2 or BB 1 receptor, despite the fact that these receptors share an 51 and 47% amino acid identity, respectively [1,32]. To investigate this in detail, a chimera receptor approach was initially used substituting extracellular domains of BB 3 receptor (high affinity, Bantag-1) with those from BB 2 receptor (low affinity, Bantag- 1) resulting in potentialaBantag-1 loss-of-affinity chimeras.…”

“…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.…”

Bombesin-Like Receptor 3: Physiology of a Functional Orphan

“…BRS-3 expression has been noted in multiple tumor types (lung carcinoma, carcinoid, renal cell, Ewing sarcoma, pancreatic, pituitary, ovarian, prostate) [1]. Since the tissues from which the cancers originate typically express little BRS-3, some tumor cells may upregulate BRS-3 expression.…”

“…Bombesin-like receptor 3 (BRS-3, also known as bombesin receptor subtype 3 and BB 3 ) is an orphan X-linked Gq-coupled receptor [1]. BRS-3 was named for its sequence similarity to receptors binding bombesin, a 14-amino acid frog peptide.…”

“…Since the conditions regulating endogenous ligand production are unknown, the physiologic conditions causing BRS-3 activation are also unknown and it has been difficult to study effects of receptor activation. The welcome discovery of potent, selective synthetic ligands facilitated study of BRS-3 physiology (reviewed in [1]). However, without an endogenous ligand, one cannot know if the effects of synthetic probes faithfully mimic endogenous physiology, reflect unanticipated ligand properties (e.g., biased agonism), or occur only with supra-physiologic pharmacologic doses.…”