Mammalian bombesin receptors

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131

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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confidence: 99%

Rational Design of a Peptide Agonist That Interacts Selectively with the Orphan Receptor, Bombesin Receptor Subtype 3

Mantey

Coy

Pradhan

et al. 2001

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131

“…These peptides mediate a spectrum of biological activities by binding to two structurally and pharmacologically distinct receptors, the NMB receptor (NMBR) and GRP receptor (GRPR) (19,20). These peptides have important effects in the central nervous system including thermoregulation (21), satiety (22), control of circadian rhythm (23), and in peripheral tissues causing stimulation of gastrointestinal hormone release (18,24,25), activation of macrophages (26), and effects on development (27,28).…”

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confidence: 99%

“…These peptides also have potent growth effects causing proliferation of normal cells (18,29) and various tumor cell lines (18,30). The NMBR and GRPR are members of the bombesin receptor family within the GPCR superfamily and share ϳ50% overall amino acid sequence identity (19,20). Both the NMBR and GRPR are widely distributed in the central nervous system and alimentary tract (18).…”

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confidence: 99%

“…Both the NMBR and GRPR are widely distributed in the central nervous system and alimentary tract (18). Although the potential physiological role of GRP and its receptor has been a major focus of research (18,20), the role of NMB in physiological or pathophysiological processes has received much less attention. Some studies suggest that NMB may play an important role in a number of biological processes, including causing growth of some tumor cells (31), a modulatory role in suppression of feeding behavior or gastric emptying (32), con-trol of the hypothalamic-pituitary-adrenocortical axis and thyrotropin release (33), sensory transmission in the spinal cord (34), excitation of serotonin neurons in the dorsal raphe nucleus (35), control of potassium secretion by the blood-brain barrier (36), and smooth muscle contractility (37).…”

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confidence: 99%

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Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368

Tokita¹,

Hocart²,

Katsuno³

et al. 2001

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Peptoid antagonists are increasingly being described for G protein-coupled receptors; however, little is known about the molecular basis of their binding. Recently, the peptoid PD168368 was found to be a potent selective neuromedin B receptor (NMBR) antagonist. To investigate the molecular basis for its selectivity for the NMBR over the closely related receptor for gastrin-releasing peptide (GRPR), we used a chimeric receptor approach and a site-directed mutagenesis approach. Mutated receptors were transiently expressed in Balb 3T3. The extracellular domains of the NMBR were not important for the selectivity of PD168368. However, substitution of the 5th upper transmembrane domain (uTM5) of the NMBR by the comparable GRPR domains decreased the affinity 16-fold. When the reverse study was performed by substituting the uTM5 of NMBR into the GRPR, a 9-fold increase in affinity occurred. Each of the 4 amino acids that differed between NMBR and GRPR in the uTM5 region were exchanged, but only the substitution of Phe 220 for Tyr in the NMBR caused a decrease in affinity. When the reverse study was performed to attempt to demonstrate a gain of affinity in the GRPR, the substitution of Tyr 219 for Phe caused an increase in affinity. These results suggest that the hydroxyl group of Tyr 220 in uTM5 of NMBR plays a critical role for high selectivity of PD168368 for NMBR over GRPR. Receptor and ligand modeling suggests that the hydroxyl of the Tyr 220 interacts with nitrophenyl group of PD168368 likely primarily by hydrogen bonding. This result shows the selectivity of the peptoid PD168368, similar to that reported for numerous non-peptide analogues with other G protein-coupled receptors, is primarily dependent on interaction with transmembrane amino acids.

“…They regulate various physiological processes such as secretion, growth, muscle contraction, and neuromodulation through high affinity receptors (1,2). Three pharmacologically and structurally distinct bombesin receptor subtypes have been cloned and characterized in mammals as follows: the GRP-preferring receptor (GRP-R), the neuromedin B-preferring receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3) which has a structure related to GRP-R and NMB-R but for which no high affinity, naturally occurring ligand has been identified as yet (2). Comparison of the predicted amino acid sequences (2) of the bombesin receptor subtypes shows all three to be structurally related members of the G protein-coupled receptor superfamily with pairwise sequence identity ranging from 48 to 54% (see Fig.…”

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The Bombesin Receptor Subtypes Have Distinct G Protein Specificities

Jian

Sainz

Clark

et al. 1999

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We used an in situ reconstitution assay to examine the receptor coupling to purified G protein ␣ subunits by the bombesin receptor family, including gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3). Cells expressing GRP-R or NMB-R catalyzed the activation of squid retinal G␣ q and mouse G␣ q but not bovine retinal G␣ t or bovine brain G␣ i/o . The GRP-R-and NMB-R-catalyzed activations of G␣ q were dependent upon and enhanced by different ␤␥ dimers in the same rank order as follows: bovine brain ␤␥ > ␤ 1 ␥ 2 > > ␤ 1 ␥ 1 . Despite these qualitative similarities, GRP-R and NMB-R had distinct kinetic properties in receptor-G protein coupling. GRP-R had higher affinities for bovine brain ␤␥, ␤ 1 ␥ 1 , and ␤ 1 ␥ 2 and squid retinal G␣ q . In addition, GRP-R showed higher catalytic activity on squid G␣ q . Like GRP-R and NMB-R, BRS-3 did not catalyze GTP␥S binding to G␣ i/o or G␣ t . However, BRS-3 showed little, if any, coupling with squid G␣ q but clearly activated mouse G␣ q . GRP-R and NMB-R catalyzed GTP␥S binding to both squid and mouse G␣ q , with GRP-R activating squid G␣ q more effectively, and NMB-R also showed slight preference for squid G␣ q . These studies reveal that the structurally similar bombesin receptor subtypes, in particular BRS-3, possess distinct coupling preferences among members of the G␣ q family.Mammalian bombesin-like peptides, gastrin-releasing peptide (GRP) 1 and neuromedin B (NMB), are widely distributed in the nervous system and the gut. They regulate various physiological processes such as secretion, growth, muscle contraction, and neuromodulation through high affinity receptors (1, 2). Three pharmacologically and structurally distinct bombesin receptor subtypes have been cloned and characterized in mammals as follows: the GRP-preferring receptor (GRP-R), the neuromedin B-preferring receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3) which has a structure related to GRP-R and NMB-R but for which no high affinity, naturally occurring ligand has been identified as yet (2). Comparison of the predicted amino acid sequences (2) of the bombesin receptor subtypes shows all three to be structurally related members of the G protein-coupled receptor superfamily with pairwise sequence identity ranging from 48 to 54% (see Fig. 1). Upon agonist binding, G protein-coupled receptors activate specific heterotrimeric G proteins, which in turn regulate a variety of intracellular effectors such as adenylyl cyclase, phospholipase C, ion channels, and cGMP-phosphodiesterase (3).Heterotrimeric G proteins are composed of three polypeptides as follows: an ␣ subunit and a ␤␥ dimer that acts as a functional monomer. Ligand-activated G protein-coupled receptors catalyze the exchange of GTP for GDP bound to the G␣ subunit, resulting in dissociation of the GTP-activated ␣ subunit from both its cognate G␤␥ dimer and the receptor. The GTP-activated ␣ subunit as well as dissociated G␤␥ dimer in turn regulate intracellular effectors. At least 20 d...