Bombesin Receptors

Bombesin is a 14 amino acid peptide isolated from frog skin. The mammalian counterparts of the frog peptide are neuromedin B (NMB) and gastrin-releasing peptide (GRP), as well as the biologically active GRP fragment neuromedin C (NMC). The first two receptors for these ligands to be cloned were designated BB1 and BB2, and were originally referred to as the NMB- and GRP-preferring bombesin receptors, after their respective endogenous ligands. A third mammalian bombesin receptor subtype, BB3 (also known as BRS3), was cloned and a fourth bombesin receptor, BB4, has been cloned from the frog. All the receptor subtypes couple via Gq/11 to the phospholipase C signaling pathway. Each also activates phospholipase D and stimulates tyrosine phosphorylation of numerous proteins (p125FAK, paxillin, others).

Bombesin receptor pharmacology was originally defined in terms of the rank order of potency of the endogenous ligands NMB, GRP and bombesin, with the rank order of potency being NMB> bombesin> GRP at the BB1 receptor and GRP> bombesin> NMB at the BB2 receptor. Further characterization became possible with the development of a range of peptide GRP antagonists. Two non-peptide BB1 selective antagonists, PD 165929 and PD 168368, have been reported that possess affinities of 7.6 nM and 30 nM at the BB1 receptor, respectively. PD 165929 is inactive at the BB2 receptor, while PD 168368 has an affinity at this receptor of 1.2 µM. However, both compounds require solubilization in cyclodextrin, thus limiting their use in vivo. BB3 has low affinity for all naturally occurring bombesin-related peptides and its native ligand is unknown.

Bombesin receptors play a role in a variety of physiological and pathological processes in mammals, although the precise subtype(s) involved are not always established in each case. Both BB1 and BB2 receptors are widely distributed in the CNS as well as in the gastrointestinal tract and reproductive organs. In the CNS, bombesin-like peptides induce satiety, possibly via an interaction with corticotrophin-releasing factor. They also play a role in thermoregulation and induce histamine-independent pruritus. In addition, these peptides act via the BB2 receptor in the suprachiasmatic and dorsal raphe nuclei to regulate circadian rhythms and the activity of the serotonergic system, resulting in an association with sleep disorders and depression. Recent studies show these peptides acting via BB2 receptors are important in the regulation of emotionally motivated learning and memory. NMB functions as an autocrine regulator of TSH release by the pituitary and its release can be altered in hyper- or hypothyroid states. In the gastrointestinal tract, these peptides regulate smooth muscle contractility, pancreatic secretion, and the release of many other gastrointestinal peptides/hormones. Bombesin-like peptides also have a developmental role in the lung and the uterus. They function as potent growth factors for both normal and neoplastic tissues including lung, prostate, gastric and colonic cancers. Evidence suggests that the carcinogenic properties of these peptides are predominantly mediated by the BB2 receptor. These peptides stimulate natural killer cell activity and chemotaxis. Studies also suggest a possible role of bombesin peptides acting via the BB2 receptors in gut/lung inflammatory reactions and reaction to oxidative stress as well as CNS disorders (autism, anxiety disorders). Using knockout strategies it has been shown that mice lacking either the BB1 or BB2 receptor do not display any gross phenotypic changes from the wild type, while the BB3 receptor knockouts exhibited an obese phenotype. Using knockout mice, both BB2 and BB3 receptors are shown to be important for insulin release by islets: BB2 in satiety, BB1 in regulating 5-HT neuronal activity in the dorsal raphe nucleus, and bombesin receptors may be involved in modulating emotion in some forms of anxiety.

 

The Table below contains accepted modulators and additional information.

 

Currently Accepted Namea BB1 BB2 BB3
Alternate Name Neuromedin B-preferring (NMB-R) GRP-preferring (GRP-R) BRS3
Structural Information 390 aa (human) 384 aa (human) 399 aa (human)
Subtype Selective Agonists NMB (N3762) > Bombesin (B4272) > GRP (G8022)
GRP (G8022) > Bombesin (B4272) > NMB (N3762)
Ac-Phe-Trp-Ala-His(τβZ1)-
Nip-Gly-Arg-NH2
Subtype Selective Antagonists PD 168368
PD 165929
BW 1023U90
[D-Phe6,Cpa14-ψ13-14]-Bombesin(6-14)
[D-Phe6]-Bombesin(6-13) ethyl ester
Not Known
Receptor Selective Antagonists [Leu13-(y-CH2NH)-Leu14]-Bombesin
[Tyr4-D-Phe12]-Bombesin
ICI 216,140 (I123)
[Leu13-(y-CH2NH)-Leu14]-Bombesin
[Tyr4-D-Phe12]-Bombesin
ICI 216,140 (I123)
Not Known
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG)
Radioligands of Choice [125I]-BH-NMB; 125I-D-Tyr0]NMB
[125I]-[Tyr4]-Bombesin
[125I]-[D-Tyr6,β-Ala11,Phe13,Nle14]-Bombesin(6-14)
[125I]-[D-Tyr6]-Bombesin(6-13) methyl ester
[125I]-[Tyr4]-Bombesin
[125I]-[D-Tyr6,β-Ala11,Phe13,Nle14]-Bombesin(6-14)
[125I]-[D-Tyr6,β-Ala11,Phe13,Nle14]- Bombesin(6-14)
Tissue Expression CNS (olfactory bulb, central thalamic regions, amygdala)
GI tract (esp. esophagus)
Bronchial epithelial cells
Testis
Uterus
CNS (spinal sensory ganglia, hypothalamus, basal ganglia, amygdala)
GI tract
Reproductive system
lung (bronchial epithelial cells)
CNS (habenula, thalamic nuclei)
Hypothalamus
Cortex
Testis (rat)
Lung (bronchial epithelial cells)
Physiological Function TSH release
Regulation of stress response
CNS actions
Circadian rhythm control
Satiety
Regulate sympathetic nervous system
Regulate emotionally-motivated learning
Maintenance normoglycemia
Gallbladder contraction
Motility and peristaltic wave regulation
Pancreatic secretion
Acid secretion regulation
Islet function
Potent stimulant release of numerous GI hormones
Regulate energy
Glucose homeostasis
Disease Relevance Autocrine function (altered in hypo-/hyperthyroidism)
Growth factor
Some tumors
Regulation of stress response
CNS disorders (autism, anxiety)
Gut/ lung inflammatory disorders
Growth factor
Numerous tumors (prostate, lung, gastric, colon)
Broncho-pulmonary dysplasia
Tobacco-related injury
Knockout mice obese
Develop glucose intolerance

 

Footnote

a) A bombesin receptor comprising 377 aa has been cloned in frog. Referred to as a BB4 receptor, it displays relative agonist potencies of [Phe13]-bombesin > GRP > NMB, is blocked by [D-Phe6]-bombesin (6-13) propylamide and can be radiolabeled using [125I]-[Tyr4]bombesin.

 

Abbreviations

BW 1023U90: N-[3-(4-Hydroxyphenyl)-1-oxopropyl]-L-histidyl-L-tryptophyl-L-alanyl-L-valyl-N-[(1S)-2-[(2R)-2-[[[(1S)-2-amino- 2-oxo-1-(phenylmethyl)ethyl]amino]methyl]-1-pyrrolidinyl]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-D-alaninamide
GRP: Gastrin releasing peptide
ICI 216,140: (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3
Nip: Piperidine 3-carboxylic acid
NMB: Neuromedin B
PD 165929: 2-[3-(2,6-Diisopropyl-phenyl)-ureido]3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionate
PD 168368: 3-(1H-Indol-3-yl)-2-methyl-2-[3(4-nitrophenyl)-ureido]-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide
PD 176252: 3-(1H-Indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(4-nitro-phenyl)-ureidol]-propionamide
PhPr: Phenylpropanoyl

 

References