Bombesin receptors: Introduction

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General

The bombesin (Bn) receptor family is a member of the G protein-coupled receptor superfamily and consists of three subtypes of receptors: the neuromedin B (NMB) receptor (BB1 receptor), the gastrin-releasing peptide (GRP) receptor (BB2 receptor) and the orphan receptor, bombesin receptor subtype 3 (BRS-3) (BB3 receptor) [57,87,92,122]. The unusual name of this class of receptors comes from the fact that bombesin and many of the other naturally occurring peptides in this peptide family were isolated from the skin of various frogs and were named after the genus of the frog from which they were isolated [42-43]. The first two receptors bind with high affinity the mammalian ligands NMB (BB1 receptor) and GRP (BB2 receptor), respectively, as well as bombesin and a number of the other peptides isolated primarily from the skin of various frogs (litorin, ranatensin, alytesin, etc) [42-43,229] and numerous synthetic analogues of Bn/GRP/NMB [87,249]. BB3 is an orphan receptor, with a high degree of homology to the BB1 and BB2 receptors [44], but has an unknown natural ligand because it has low affinity for all naturally occurring bombesin-related peptides [87,129,249]. These receptors are widely distributed in mammals especially in the CNS and gastrointestinal tract and have numerous effects both physiologically and in pathologic processes including having an autocrine growth action on normal tissues and tumors; potent CNS effects (satiety, circadian rhythm, various behaviours): and potent effects in the immune, gastrointestinal, respiratory and urogenital systems [17,57,87,91-92,103,122,278]. It has been proposed that they may be important in a number of human disorders including growth of human cancers; as biomarkers for diseases such as non-small cell and small cell lung cancer; in regulating energy homeostasis and obesity; in various CNS diseases including memory loss, anxiety and behavior disorders, and in inflammatory disorders such as arthritis, uveitis and sepsis [27,57,87,91-92,103,122-124,180,182,201-202].

GRP

GRP is a 27-amino acid peptide that was isolated in 1978 from porcine nonantral gastric tissue [135] and was named for its ability to stimulate gastrin release. GRP differs from the frog tetradecapeptide, bombesin, in only one amino acid in its last 10 carboxyl-terminal residues, which is its biologically active end. For a number of years GRP was thought to be the mammalian equivalent of frog bombesin, however Xenopus laevis has been shown to produce a 29 amino acid peptide homologous to mammalian GRP, and the same frog has been shown to express different mRNAs to encode both bombesin and GRP [98,158,229]. A single human GRP-encoding gene has been described and is located on chromosome 18q21 [112,160,229]. Three different mRNA species are identified in humans generated through alternative splicing that encode precursors of slightly different chain lengths [5]. The gene comprises three exons and two introns and the second intron possesses the alternate donor site, which is used to produce the three mRNAs [216]. The human GRP mRNA encodes for a precursor of 148 amino acids that contains a signal sequence [230]. GRP1-27 is formed by multiple enzymatic cleavages at both the amino terminus and the carboxyl terminal extended portion of the precursor. GRP1-27 can be processed further to give GRP10-27 [193] (which was originally termed neuromedin C) [145]. GRP is found widely, especially in the CNS and the gastrointestinal tract [86,103,113]. In the gastrointestinal tract it is found in nerve fibers and cell bodies, especially of the myenteric plexus as well as the submucosal plexus and in sympathetic prevertebral ganglia. The highest levels are found in gastric fundus, antrum and pylorus [188]. In the CNS GRP immunoreactivity is widespread in cell bodies of the cortex, pons, hypothalamus, nucleus of the solitary tract, superior olivary nucleus, nerve fibers in the thalamus, amydala, dorsal vagal nucleus and in the spinal sensory ganglia [4,86,103,152,254]. GRP has a wide range of actions, which will be briefly discussed below in the physiology and pathophysiology sections.

NMB

NMB is a decapeptide which was originally isolated from porcine spinal cord [144] and is the mammalian equivalent of the frog peptide ranatensin, to which it has an almost identical COOH terminus with six of seven amino acid identities [162]. The location of the human NMB gene is chromosome 15q11 [62,100]. NMB is encoded as a prepro-NMB, a 76 amino acid precursor that consists of a 24 amino acid signal peptide, NMB-32 and a 17 amino acid carboxyl terminal extension peptide [100]. The predicted amino acid sequence for NMB-32 is highly conserved in human, rat and pig with only differences of four amino acids [162,254]. The NMB gene is encoded in three exons and studies on rat and human genomic DNA are consistent with only a single NMB gene present. In the human Northern blot analysis reveals high expression in the hypothalamus, colon, stomach and low levels in the pancreas, cerebellum and adrenals [162]. By in situ hybridization studies NMB mRNA was found in rat brain in the greatest amounts in the olfactory bulb, dentate gyrus and dorsal root ganglion [254]. NMB has a wide range of physiological and pharmacological effects and these will be discussed later.

Bombesin Receptor Subtypes: General

In early binding/pharmacological and biological studies of bombesin-related peptides, bombesin or synthetic analogues of bombesin were almost invariably used as the agonist ligands and radiolabeled probes [87]. While some studies suggested that more than one receptor subtype might mediate the action of these peptides, it was not until 1989 that firm pharmacological and functional data convincingly demonstrated more than one subtype [87,252-253]. The failure to earlier demonstrate receptor subtypes occurred primarily because the affinity of bombesin and many of the synthetic analogues used is relatively high for both BB1 and BB2 receptors and very low for BB3 receptors, making it difficult to distinguish these subtypes with these ligands [58,87,249]. In 1989, using subtype specific antagonists as well as selective agonists such as NMB and GRP [252-253], both BB1 receptors and BB2 receptors were shown to exist in rat tissues. Both were subsequently cloned [5,231,255], as was the BB3 receptor [44,92].

BB1 Receptor

The human BB1 receptor [8,195,249], and the rat BB1 receptor [9,106,114,206,252-253,258] have a greater than 100-fold higher affinity for NMB than GRP. In one recent study comparing both native and transfected human BB1 receptors and human BB2 receptors [249], NMB had >600-fold selectivity for the human BB1 receptor over the human BB2 receptor. Bombesin and the frog peptides ranatensin and litorin also have relatively high affinity for the BB1 receptor [96,114,129,249,256], as does the synthetic bombesin analogue [D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14) [129,187,195,249]. The rat BB1 receptor was cloned in 1991 [255], followed by the cloning of the human BB1 receptor [25].

The human BB1 receptor is a 390 amino acid protein and shows an 89% amino acid identity with the rat BB1 receptor. It has 55% amino acid identities with the human BB2 receptor and 47% with the human BB3 receptor [87]. It was subsequently cloned from mouse [164], monkey [215] and the frog Bombina orientalis [157]. The human BB1 receptor gene is at chromosome 6p21-pter and contains three exons and two introns [25,87,164,255]. The human BB1 receptor has three potential N-linked glycosylation sites. The mature receptor is glycosylated having a molecular weight of 72 kDa and the deglycosylated receptor is 43 kDa [8]. Detailed studies in the rat BB1 receptor demonstrate each potential N-linked glycosylation site is glycosylated with tri- and or tetra-antennary complex oligosaccharide chains and the mature receptor is a sialoprotein [101].

Expression levels have been reported in human, rat, mouse and monkey [25,87,164,255]. In the monkey [215] the highest levels of BB1 receptor are in the testis and stomach as well as in the CNS including the amydala, caudate nucleus, hippocampus, hypothalamus, thalamus, brain stem and spinal cord. BB1 receptors also occur on a large number of different tumors [113,195] including CNS tumors as well as tumors of the lung, ovary, pancreas and carcinoids [87].

There are few specific receptor antagonists for the BB1 receptor [58,87]. The peptoid antagonist PD 168368 has the highest affinity and selectivity for the BB1 receptor. PD 168368 has a high affinity (Ki 0.25-0.51 nM) for the BB1 receptor from humans and rat (Ki 39 nM), a 2250-fold lower affinity for human BB2 receptor and 33-fold lower affinity for the rat BB2 receptor and a >20,000 fold lower affinity for the human BB3 receptor [58,87,206,247].

BB2 Receptor

The human BB2 receptor [8,50,195,249], as well as the rat [96,106,114,252], mouse [6,80,206,246,248], and guinea pig BB2 receptors [89,125] have a greater than 50-fold higher affinity for GRP than NMB. In a recent study [249] using both native human BB2 receptor containing cells and BB2/BB1 receptor transfected cells, GRP had >2500 higher affinity for the human BB2 receptor than the human BB1 receptor. Bombesin and numerous frog peptides also have a high affinity for the BB2 receptor [89,96,249], as do a number of synthetic bombesin analogues including [D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14) [129,187,195,249], which also has a high affinity for the BB1 receptor [129,151,187] and human BB3 receptor [129,151,187].

In 1990 the mouse BB2 receptor was the first bombesin receptor to be cloned [5,231], closely followed by the cloning of the human BB2 receptor [25]. The BB2 receptor has now been cloned or partially characterized in 21 species [3]. The human BB2 receptor is a 384 amino acid protein and shows a high degree of homology with the mouse receptor with 90% amino acid identities [25]. It has 55% amino acid identities with the human BB1 receptor and 51% with the human BB3 receptor [44,87]. The human BB2 receptor has two sites for potential N-linked glycosylation and the mouse BB2 receptor has four [5,25,231]. The mature murine BB2 receptor is 82 kDa, the mature human BB2 receptor is 60 kDa and the deglycosylated forms are 43 kDa [8,101]. For the murine BB2 receptor, detailed serial deglycosylation studies as well as mutagenesis studies altering the N-linked glycosylation sites combined with receptor cross-linking studies and expression of the receptor in baculovirus have been carried out [7,101-102]. These studies demonstrate the murine BB2 receptor is glycosylated at each of the four potential N-glycosylation sites with tri- or tetra-antennary complex oligosaccharide chains, the length of which various from 5-12 kD and that the receptor is not a sialoprotein, contains no O-linked glycosylation and the extent of the glycosylation affects receptor expression [7,102,157]. The human BB2 receptor gene is located at Xp22 and contains three exons and two introns [25,131,266].

Expression levels of the BB2 receptor have been reported in human, mouse and monkey [4-5,25,215,231]. In the monkey [215], where BB2 receptor distribution has been studied in detail, the highest levels of the BB2 receptor are in the pancreas, with lesser amounts in the stomach, prostate, skeletal muscle and CNS. In monkey CNS [215] BB2 receptor mRNA is widely expressed with the highest amounts in the hippocampus, hypothalamus, amydala and pons. Detailed mapping studies are also reported in the rat brain, where BB2 receptor mRNA is found in all regions, with the highest amount in the hypothalamus, particularly the suprachiasmatic and supraoptic nuclei as well as in the magnocellular preoptic nucleus in the basal ganglia and the nucleus of the lateral olfactory tract [4]. Mapping studies using a specific BB2 receptor antibody confirmed widespread distribution in the rat brain, showing especially strong immunoreactivity in the nuclei of the amygdala and in the nucleus tractus solitarius [94].

BB2 receptors are one of the most frequently over-expressed or ectopically expressed receptors on human cancers [27,90-92,175]. They have been widely studied and are frequently present in cancers of the lung, prostate, breast, head and neck, colon, uterus, CNS, ovary and kidney [90-92,175,195]. In various studies BB2 receptors are present on 85-100% of small cell lung cancers, 74-78% of non-small cell lung cancers, 38-72% of breast cancers, 75% of pancreatic cancers, 62-100% of prostate cancers, 100% of head/neck squamous cell cancers, 85% of glioblastomas and 72% of neuroblastomas [90-91]. In many of these cancers they have an autocrine growth effect [30,90-92,111,185,225,259].

There are a number of different peptide and two nonpeptide receptor antagonist classes reported for the BB2 receptor, some of which have high affinity and high selectivity for the BB2 receptor [33,58,87-88]. They can be divided into twelve chemical classes of BB2 receptor antagonists [58,87]. All classes are peptides or peptoid antagonists, except the two nonpeptide classes [33,58,87-88]. One nonpeptide class is composed of flavone derivatives (kuwanon G and H) isolated from extracts of the mulberry tree Morus bombycis [142] and the other two oxindole derivatives (CP-070,030,CP-75,998) [250]. Each of the classes of nonpeptide antagonists has low affinity (IC50>1 µM) for the BB2 receptor. These twelve classes include D-amino acid substituted substance P analogues; [D-Phe12]bombesin analogues; bombesin modified at position 13-14 or GRP modified at position 26-27; desMet14 or GRP27 ester analogues; desMet14 or GRP27 alkylamide analogues; [D-Pro13, ψ13-14 pseudo-bond] peptide analogues; D-amino acid substituted somatostatin analogues; cyclic bombesin peptide analogues; peptoids and finally the nonpeptide analogues, kuwanon G and H and CP-070,030/CP-75,998 [28,33,58,72,87-88,142,248,250,253,257].

BB3 Receptor

Prior to the identification of the BB3 receptor when it was cloned in 1992 from the guinea pig uterus [59], no pharmacological or functional data suggested its presence. The BB3 receptor has now been cloned from rat [117], mouse [164], sheep [263], monkey [215] and human [44]. Each of these receptors, when expressed, have low affinity for the mammalian peptides GRP and NMB, and in the case of the human BB3 receptor, it was shown to have low affinity for all known naturally occurring bombesin related peptides [117,124,129,206,208,249,265]. Therefore at present the natural ligand of this receptor is unknown.

The human BB3 receptor is a 399 amino acid protein [44] and it shows 95% amino acid identities with the monkey [215] and 80% with the rat BB3 receptor [87]. The human BB3 receptor has 47% amino acid identities with the human BB1 receptor and 51% with the human BB2 receptor [44]. The human BB3 receptor has a predicted molecular weight of 44.4 kDa and has two potential N-linked glycosylation sites, but there are no cross-linking studies of the mature BB3 receptor.

The human BB3 receptor gene is located at chromosome Xq25 and in the mouse at XA7.1-7.2 [44,60,262]. The human BB3 receptor gene contains two introns and three exons [44,262].

Expression levels of the BB3 receptor mRNA are reported in rat, sheep, mouse, monkey and guinea pig [39,44,59,84,117,215,250,263]. Detectable amounts are found in the monkey thyroid, pancreas and ovary [215]. Detailed studies show that BB3 receptor mRNA is present in the islets in multiple species including human [45]. In the CNS BB3 receptor mRNA is expressed in a more restricted distribution than BB1 receptor or BB2 receptor [39,84,117,215], although in a recent study it is more widely distributed [276]. In the rat and mouse [39,117,276] and in the monkey brain BB3 receptor mRNA is present in the highest amounts in the hypothalamus [215,276] and is particularly high in the preoptic nucleus, the PVN, the dorsomedial hypothalmic nucleus and the arcuate nucleus, supporting the hypothesis that the BB3 receptor may be important for the hypothalamic regulation of energy homeostasis [276]. In the monkey brain BB3 receptor mRNA is present in the highest amounts, after the hypothalamus [215], in the pituitary gland, amygdala, hippocampus and caudate nucleus [215]. In the mouse and rat brains [276], no BB3 receptor mRNA can be detected in the cerebral cortex, olfactory bulb, hippocampal formation, cerebellum, substantia nigra or ventral tegmental area. In rat and mouse brains [276], double in situ hydridization studies show that BB3 receptor mRNA colocalizes frequently with glutamatergic neurons, and to a lesser extent with cholinergic or GABAergic neurons, and CRF or GHRH, but not with NPY, POMC, orexin/hypocretin, MCH,GnRH or kisspentin. Specific BB3 receptor antibodies have been used to localise the receptor in the tunica muscularis of the gastrointestinal tract [186] and in the rat CNS [84]. In the gastrointestinal tract the BB3 receptor was detected in myenteric and submucosal ganglia as well as the interstitial cells of Cajal [186]. In the CNS particularly strong staining was detected in the cerebral cortex, hippocampus, hypothalamus and thalamus [186].

The natural ligand for the BB3 receptor remains unknown. Recently two Drosphilia G-protein coupled receptors (CG30106,CG14593) have been identified and belong to the BB3 receptor family [69,74,81]. These receptors interact with two ligands CCHamide-1[SCLEYGHSCWGAH-NH2] and CCHamide-2[GCQAYGHVCYGGH-NH2], which when administered to blowflies increased feeding [81]. Unfortunately, neither of the CCHamide peptides activated the BB3 receptor[81] and each was found to have a very low affinity for the human BB3 receptor (Jensen, unpublished data). Using a bacterial two-hybrid system, the BB3 receptor was found to interact with a novel 354 amino acid protein, named bombesin receptor activated protein (BRAP) [115]. BRAP is found in both the cellular cytoplasm and nucleus, its expression promotes G1 to S phase transition, accelerates DNA snythesis, and promotes the proliferation of bronchial epithelial cells [115]. This has led to the proposal that BRAP may be important in BB3 receptor mediated changes in cell cycle regulation and in wound healing in bronchial epithelial cells [115]. Overexpression of BRAP [191] in bronchial epithelial cells inhibits the ability of these cells to take up antigen suggesting it may play an important role in the antigen presenting process of bronchial epithelium.

Even although no high affinity natural ligands exist for this receptor it has been found that the synthetic bombesin ligand, [D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14) binds and activates both cells containing the natural occurring [208] and expressed BB3 receptors with high affinity/potency [129,187,206-207,249]. When the rat BB3 receptor was cloned [117] it was surprisingly found that [D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14) had low affinity for this receptor, whereas it had high affinity for the monkey BB3 receptor, similar to the human receptor [215]. Using a chimeric receptor approach [117] in which the individual extracellular loops of the rat BB3 receptor were replaced with the corresponding human sequences the important residues were localised to the 4th extracellular domain (1st=N-terminus). Within this region, using site-directed mutagenesis [117], the mutation of Y298E299S330 (rat) to S298Q299T300 (human) or of D306V307H308 (rat) to A306M307H308 (human) partially mimic the effect of switching the entire 4th extracellular domain. These results indicate that variations in the 4th extracellular domains of the rat and human BB3 receptor are responsible for the differences in affinity for [D-Phe6,β-Ala11,Phe13,Nle14]bombesin6-14 [117].Subsequent studies demonstrated the synthetic bombesin analogue, [D-Phe6,β-Ala11,Phe13,Nle14]bombesin6-14, in addition to having high affinity for monkey and human BB3 receptors, also had high affinity for all BB1 and all BB2 receptors, as well as a frog BB4 subtype which is not found in mammals [129,154,187,206-208,249]. Due to the lack of selectivity of the high affinity agonist, [D-Phe6,β-Ala11,Phe13, Nle14]bombesin6-14 for the human BB3 receptor, a number of groups have attempted to develop more selective BB3 receptor ligands. In one study [127] rational peptide design was used by substituting conformationally restricted amino acids and a number of BB3 receptor selective agonists were identified with two peptides with either an (R) or (S)-amino-3-phenylpropionic acid substitution for β-Ala11 in the prototype ligand having the highest selectivity (i.e.17-19-fold) [127]. Molecular modeling demonstrated these two selective BB3 receptor ligands had a unique conformation of the position of the 11 β-amino acids, which likely accounted for their selectivity [127]. In a second study [126] two strategies were used to attempt to develop a more selective BB3 receptor ligand: substitutions on the phenyl ring of Ala11 and the substitution of additional conformationally restricted amino acids into the position 11 of [D-Phe6,β-Apa11,Phe13,Nle14]bombesin6-14 or its D-Tyr6 analogue. One analogue, [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin6-14 retained high affinity for BB3 receptor and was 227-fold selective for the BB3 receptor over the human BB2 receptor and 800-fold selective over the human BB1 receptor [126]. Using [D-Phe6,β-Ala,sup>11,Phe13,Nle14]bombesin6-14 or its D-Tyr6 analogue as the prototype, three studies [15,260-261] reported shortened analogues with selectivity for BB3 receptor assessed by calcium or FIPR calcium assays. A recent study has assessed the selectivity of four of the most selective of these shortened [D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14) analogues by binding assays as well as assessment of phospholipase C potencies [128]. Only the novel compound Ac-Phe,Trp,Ala,His(tBzl),Nip,Gly,Arg-NH2 (compound 34 in reference [15]) had a 14-fold higher affinity for BB3 receptor than BB1 receptor and >20 fold for BB2 receptor [128], however it was less BB3 receptor selective than [D-Tyr6,Apa-4Cl11,Phe13,Nle14] bombesin6-14 (i.e. >100 fold selectivity) [126,128].

Recently a number of BB3 receptor nonpeptide agonists have been described including derivatives of omeprazole [20], benzodiazepine sulfonamide analogues [24], derivatives of an analogue found to have activity during high throughput screening [7-benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]- [2,7]naphthyridin-1-ylamine] [66-67], substituted biphenyl imidazole analogues [70], 2-biarylethylimidazole analogues [116], pyridinesulfonylureas and pyridinesulfonamide analogues [120]. Of these the selective nonpeptide high affinity agonist, MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-[[1-(trifluoromethyl)cyclopropyl] methyl]-1H-imidazol-2-yl)propan-2-ol ] [37-39], or Bag-1, (2-(4-[2-[5-(2,2-dimethylbutyl)-1H-imidazol-2-yl] ethyl]phenyl) pyridine (compound 9 in [116]) have been the most widely used for agonist studies of the BB3 receptor. Also a high affinity selective BB3 receptor peptide antagonist, Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] has been described [45,64] MK-5046 is orally active and shown to be active in dog, mice, rat, monkey and human [65,194]. In a recent comparison of their selectivity for human BB3 receptor cells expressing native or transfected receptors, MK-50946 and Bantag-1 were found to have high affinity for the human BB3 receptor (17.7-18.8, 1-1.6 nM, resectively) and to be 555-fold and 6250-fold selective, respectively, based on affinities for the human BB3 receptor over either the human BB1 or BB2 receptor. In terms of selectivity for activation of the human BB3 receptor (phospholipase C activation), MK-5046 had a selective potency of >10,000-fold over the human BB1 and human BB2 receptors [155]. A number of studies using site-directed mutageneis have examined the molecular basis for agonist activation and selectivity for the human BB3 receptor [54,56,249]. In one study [54] epitopes determining the agonist property of [D-Tyr6,(R)-Apa-Cl11,Phe13,Nle14]bombesin(6-14) or Ac-Phe,Trp,Ala,His(tBzl),Nip,Gly,Arg-NH2 (compound 34 in reference [15]) were examined. The mutational map for Ac-Phe,Trp,Ala,His(ψBzl),Nip,Gly,Arg-NH2 spanned the entire binding pocket, whereas that for [D-Tyr6,(R)-Apa-Cl11,Phe13,Nle14]bombesin(6-14) was confined to the center of the pocket encompassing the opposing faces of the extracelluar segment of TM-111,TM-V1 and TM-VIII [54]. Using a chimeric receptor approach combined with site-directed mutagenesis [56], the selectivity of [D-Tyr6,(R)-Apa-Cl11,Phe13,Nle14]bombesin(6-14), Ac-Phe,Trp,Ala,His(ψBzl),Nip,Gly,Arg-NH2, and [D-Tyr6,(R)-Apa11,Phe13,Nle14]bombesin(6-14) for the human BB3 receptor was examined. Even though these three human BB3 receptor agonists were developed from the same template peptide, [D-Tyr6,β-Ala11,Phe13,Nle14]bombesin(6-14), their molecular determinants of selectivity/high affinity varied considerably [56].

Physiological and pathophysiological roles

A very wide range of effects have been reported with bombesin related peptides [57,90-92,103,122-124,229,278], but because of the use of nonselective ligands and lack of selective antagonists until recently, the bombesin receptor subtype mediating these effects, as well as which effects were pharmacological and which were physiological, were largely unknown [87]. Recent studies using mice with a specific receptor knockout, as well as studies using selective ligands and molecular studies have provided more detailed information on the subtypes involved [57,87,91-92,103,122-124,229].

BB1: Physiological and pathophysiological roles

Specific binding studies, as well as receptor antagonist and BB1 receptor knockout studies, provide evidence that BB1 receptor activation can stimulate contraction of urogenital and gastrointestinal smooth muscle (esophageal, gastric, colonic, gallbladder) [10,92,97,143,174,204,223,252-253]; potently inhibit thyrotropin release acting as an autocrine/paracrine regulator [168,172,177-179] [92,167]; have potent CNS effects including inhibiting food intake independent of BB2 receptor stimulation and energy metabolism [78,92,103,108-110,140,176]; thermoregulation [163]; mediate aspects of the stress response, fear response [18]; various behaviours such as spontaneous activity [18,138-139,270-271]; in pain and itch sensation [47,146]; scratching behavior [235]; and is important in memory and learning [270]. The BB1 receptor is frequently over-expressed by various tumors [91-92,113,175,214,236] including 55% of small cell lung cancers, 67% of non-small cell lung cancers, 46% of intestinal carcinoids, 86% of ovarian cancers as well [91-92,113,133,150,195,214]. NMB has been shown to function as an autocrine growth factor in non-small cell lung cancer, small cell lung cancer cells, and in colon cancer [19,91-92,133,148,214,226]. No specific diseases have been proven to be associated with alterations in the BB1 receptor at present, but studies show that conditions with increased TSH release such as hypothyroidism are associated with decreased pituitary NMB levels [93,173], while in hyperthyroidism where the TSH levels are suppressed, there is an increased pituitary NMB level [93,172] suggesting NMB could play and important role in human thyroid disorders. It has been proposed that alterations in the neuromedin B gene (particularly a p.P73T missense mutation in the NMB beta gene or a NMB rs3809508 polymorphism) may be associated with eating disorders and susceptabilty to obesity energy intake [11,14,184,232].

BB2: Physiological and pathophysiological roles

Binding studies as well as results from BB2 receptor agonist and antagonist studies and BB2 receptor knockout studies provide evidence that BB2 receptor activation is involved in a wide range of physiological functions [17,57,86-87,91-92,103,113,122]. In the gastrointestinal tract BB2 receptor activation causes stimulation of acid secretion, as well as pancreatic and intestinal secretion [17,86-87,92,113,220,251] and stimulates gastrointestinal motility causing gallbladder contraction, as well as affecting antral and intestinal motility and intestinal reflexes [17,86,92,113]. GRP plays an essential role in the intestinal peristaltic reflex because it is a modulatory neurotransmitter of the descending phase of the peristaltic reflex [63]. In humans GRP infusions and the use of a specific BB2 receptor antagonist demonstrated BB2 receptor activation causes gallbladder contraction, stimulates gastric acid, biliary and pancreatic secretion, slows gastric emptying and slows small bowel transit [37,75,92,113]. In addition to stimulating tissues directly by interacting with BB2 receptors, GRP stimulates the release of a large number of hormones and neurotransmitters (cholecystokinin, gastrin, somatostatin, pancreatic glucagon, insulin, enteroglucagon, neurotensin, gastric inhibitory polypeptide) which can also have potent effects [12,17,55,86,92,113,134,264]. In addition to these endocrine effects, BB2 receptor knockout studies as well as direct stimulation studies demonstrate GRP interaction with BB2 receptors contributes to insulin secretion by activation of autonomic nerves at the ganglionic level as well as by direct effects on the islet [1,61,73,95,181]. Activation of the BB2 receptor in immune cells also causes a diverse number of important responses including stimulating natural killer and antibody-dependent cellular cytoxicity in leukocytes [35,38,136], chemotaxis of lymphocytes [137] and neutrophils [31], modulation of phagocytic function in macrophages [34] and chemoattractant effects in monocytes [205]. BB2 receptors are reported to be important for fetal lung development including lung branching and differentiation as well as a number of lung diseases, especially bronchopulmonary dysplasia [29,36,53,92,240]. BB2 receptors has have been extensively studied for their effects on satiety using both pharmacologic studies and BB2 receptor knockout mice [48,68,92,105,107,110,140]. These effects are not inhibited by capsaicin treatment demonstrating they are either mediated by capsaicin independent pathways or involve direct activation of BB2 receptor in the CNS [107]. Numerous studies demonstrate that BB2 receptors play a number of important roles in various processes in the CNS including regulation of circadian rhythm, body temperature control, grooming behaviours, modulation of fear, stress and anxiety, memory and CNS effects on gastrointestinal function including acid secretion [17,49,52,87,92,103,139,152,198-203,212,268-269]. The role of BB2 receptor activation has been studied extensively in the growth of normal and neoplastic tissues [87,113,149,175]. This widespread interest occurred after BB2 receptor activation on human small cell lung cancer cells not only resulted in growth of the tumor cells, but bombesin-like peptides were secreted by the tumor and thus it appeared to be acting as an autocrine growth factor [30,89,91-92]. Subsequent studies demonstrated such an autocrine growth effect in a large number of tumors including neuroblastomas, squamous head and neck tumors, pancreatic cancer cells, colon cancer, prostate cancer, glioblastoma cells and non-small cell lung cancer cells [90-92,113]. Furthermore, many human cancers over-express or ectopically express BB2 receptor [90-92,113,175,195]. The effects of BB2 receptor activation on different tumors may differ because detailed studies on colon cancer demonstrate the BB2 receptor has a morphogenic effect rather than a mitogenic effect [21-22,85]. BB2 receptors have been proposed to be important in the mediation of a number of human disorders including disorders of lung development such as bronchopulmonary dysplasia, various lung disorders, and the growth and differentiation of human cancers [87,113]. Recent studies suggest BB2 receptors may be particularly important in mediating male penile responses as well as pruritic responses [2,209-213,237]. A sexually dimorphic BB2 receptor system has been described in the spinal cord that is essential for regulating male sexual function including penile reflexes and ejaculation [209-213]. This system is affected adversely by stress and this raises the possibility it could be important in various psychogenic related erectile dysfunctions [212]. In BB2 receptor knockout mice reduced pruritogenic responses are found, whereas responses to other stimuli are intact (thermal, inflammatory, pain) [237]. Furthermore, pruritis in wild type mice is blocked by intrathecal adminstration of a BB2 receptor antagonist [237]. Selective ablation of BB2 receptor neurons in the spinal cord of mice results in scratching deficits in response to pruritic stimuli, but not to pain stimuli [238]. Additional studies provide evidence that glutamate acts as the neurotransmitter for BB2 receptor-sensitive and -insensitive itch synaptic transmission in mammalian spinal cord [99]; that MrgprA3-expressing neurons co-expressing GRP and MRgprC11 are important in mediating chloroquine-induced itching [118] and that the mu-opioid receptor (MOR) isoform, MOR1D can heterodimerize with the BB2 receptor in the spinal cord to mediate itching responses [119]. These studies suggest that BB2 receptors are important mediators of the itching sensation in the spinal cord [83,238,241].

BB2 receptors are one of the most frequently and widely over-expressed or ectopically expressed G protein-coupled receptors in human tumors including prostate, small cell lung cancers, non-small cell lung cancers, breast cancer, pancreatic cancer cell line, head and neck squamous cell cancers and neuroblastomas/glioblastomas [87,90-92,113,175,214]. This over-expression as well as the autocrine growth effects on many tumors is playing a potential role in a number of aspects of the treatment and management of these tumors [90-92,214]. These include efforts to inhibit the autocrine effects as well as using the BB2 receptor as targets to image the tumor as well as targets to deliver cytotoxic treatment selectively to the tumor [16,23,27,90-92,113,151,166,214,217-218,227,274-275]. Because GRP or it precursors are frequently synthesized as well as secreted by small cell lung cancers, their serum levels have been assessed in relationship to disease stage and activity, and assessment of ProGRP serum levels has been shown to play a useful role in both the diagnose and treatment of small cell lung cancers [76,161,170-171,233,239,242,273]. Because of its widespread participation in so many processes it has been proposed that the BB2 receptor could be a therapeutic target in a number of disorders. These include: as a target in CNS disorders [18,138,198-202] including psychiatric disorders (anxiety, bipolar disorder, fear related disorders, schizophrenia, autism, cognitive disorders) as well as neurological disorders (neuroprotective effect during stroke, memory disorders, treatment of brain tumors [neuroblastomas, gliomas]); as a possible target in patients with psychogenic erectile dysfunction [202,212]; human pruritic disorders [83,147,237-238,241]; in a variety inflammatory disorders [182] such as many inflammatory lung diseases (chronic obstructive lung disease, response to tobacco smoke), rheumatoid arthritis, sepsis, uveitis, inflammatory bowel disorders [26,32,169,182-183]; lung disorders such as bronchopulmonary dysplasia [36,190]; for antitumor treatment of various BB2 receptor containing neoplasms by the use of BB2 receptor antagonists, frequently combined with other cytotoxic agents or by the use of BB2 receptor specific ligands that interact with the tumoral BB2 receptor and inhibit tumoral growth due to their attachment to cytotoxic agents (doxorubicin, camptothecin derivatives) or the attached radiolabels[40,91-92,166,197,214,217,274,277]; for the treatment of prostatic hyperplasia as well as prostatic cancer [184] [40,196,214,219,228,267]; as tumor markers (especially in lung cancer) [185-188] [76,161,170,273] and the use of radiolabeled bombesin analogues to image tumors (prostate, lung, breast) [91-92,189,214,275].

A translocation on chromosome X (the BB2 receptor gene is at Xp22) 46,X,t(X;8)(p22.13;q22) which disrupts the BB2 receptor gene is reported in an individual with autism and multiple exostoses, mental retardation and epilepsy [13,82]. This raises the possibility that the BB2 receptor gene could be a candidate for causing Rett syndrome, however no alterations in the BB2 receptor gene were found in 25 unrelated Rett patients [71]. Studies carried out in other countries have not found a major role of the BB2 receptor gene in autism disorders [130,156]. The possibility that alterations in the BB2 receptor gene could be important in panic disorder has also been investigated in two studies, with a weak association (p=0.02) found in one study [77], and the other reporting no association [234].

BB3: Physiological and pathophysiological roles

Because the natural ligand of the BB3 receptor is not known and because, until only recently there was no good antagonist or selective agonist for this receptor, most of the information on the possible physiological or pathophysiological role of this receptor has come from BB3 receptor knockout studies [57,87,123-124]. In the initial study of BB3 receptor knockout mice [165] they developed mild obesity, associated with hypertension and impairment of glucose metabolism. These changes were associated with increased feeding behaviour, reduced metabolic rate increased serum leptin and hyperphagia [165]. These results suggested the BB3 receptor could play a role in energy balance, weight control and control of blood glucose levels [165]. Subsequent studies of BB3 receptor knockout mice showed they had altered taste preferences [272], perhaps contributing to increased feeding. BB3 receptors are found on normal islets [46] and BB3 receptor knockout mice have increased insulin levels [132] due to dysregulation of insulin control as well as altered glucose metabolism mainly due to impaired GLUT4 translocation in adipocytes [159].

The BB3 receptor in a double-labeled in situ hybridization study [51] was found to be expressed in CNS orexin neurons as well as many cells around these neurons. In functional studies [51] BB3 receptor agonists increase cytosolic calcium in these orexin neurons and hyperpolarize the neurons. In the presence of GABA receptor blockers, the a BB3 receptor agonist caused depolarization and increased firing frequency of the orexin neurons [51], leading to the conclusion that in the CNS, BB3 `receptor activation indirectly inhibits orexin neurons through GABAergic input as well as directly activating orexin neurons. It was proposed this pathway might serve as a novel target for the treatment of obesity [51]. In BB3 receptor knockout mice the hyperphagia response to melanin-concentrating hormone (MCH) is impaired [121] with increased MCH receptor levels in the hypothalamus suggesting this may contribute to the hyperphagia. A detailed study of factors contributing to obesity in BB3 receptor knockout mice [104] demonstrated that hyperphagia is a major factor leading to their increased body weight and hyperinsulinemia. However, a pair feeding study of BB3 receptor knockout mice [104] did not completely normalize fat distribution and plasma leptin levels suggesting there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype[104]. BB3 receptor knockout studies also suggest BB3 receptor is important in various behavioral effects such as those regulating social isolation [268] or modulating anxiety [269]. MK-5046, the recently described high affinity BB3 receptor agonist which is orally active, and highly selective for the BB3 receptor [65,194,222], or Bag-1, [45,116], have been used in a number of in vivo studies providing support for a number of the findings from the BB3 receptor knockout mice studies. Using the selective BB3 receptor nonpeptide agonist (Bag-1) and the BB3 receptor peptide antagonist (Bantag-1), the BB3 receptor, in multiple species, is found to be important in regulating glucose-stimulated insulin secretion, raising the possibility that it may have a role in the treatment of diabetes mellitus [45]. In another study [65] single doses of the BB3 receptor agonist, MK-5046 inhibited food intake and increased fasting metabolic rate in wild type, by not BB3 receptor knockout mice [65]. Furthermore, treatment for two weeks with MK-5046 [65] reduces body weight in mice and rats, causing modest increases in body temperature, heart rate and blood pressure. In dogs MK-5046 treatment results in persistent weight loss, accompanied by increases in body temperature and heart rate [65]. These results show an anti-obesity effect of MK-5046 in rodents and dogs and support the possible use of BB3 receptor agonism as an approach to the treatment of obesity [64-65]. These studies as well as others [141], demonstrate that BB3 receptor activation can regulate body temperature, similar to effects previously described for the BB2 receptor [87].

Recent studies show BB3 receptors are expressed in developing and fetal lungs [41,224] and are up-regulated in response to injury [190,243-244]. The BB3 receptor is reported to occur in skeletal muscle [192] and to be down regulated in skeketal muscle cells or myoctes from obese subjects or patients with diabetes mellitus. Furthermore, differences in the effects of a BB3 receptor agonist on skeletal muscle cells/myocytes [192] from normal, obese, and diabetic subjects in GLUT4 extent, location, and glucose transport have been reported, leading to the proposal that these alterations in BB3 receptor expression/responsiveness in skeletal muscle cells could be important in the metabolic response to obesity/diabetes mellitus [192]. Although the function of BB3 receptor in the gastrointestinal tract is largely unknown, BB3 receptor have been detected in myenteric and submucosal plexi as well as the interstitial cells of Cajal, leading the authors to propose that the BB3 receptor is likely involved in the regulation of gastrointestinal motility [186]. Lastly, BB3 receptors are ectopically or over-expressed in a number of human tumors [44,113,195,221,236,245] and activation of the BB3 receptor has been shown to increase MAP kinase activation, nuclear oncogene expression and adhesion of lung cancer tumor cells which is proposed to contribute to increased tumor invasion by these tumors [79]. BB3 receptor activation in lung cancer cells [153] stimulates their growth as a result of EGF receptor transactivation and the transactivation is mediated by activation of Src family kinases and generation of reactive oxygen species.

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