International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states

Abstract

The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB(1)), the gastrin-releasing peptide (GRP) receptor (BB(2)), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB(3)). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB(3) has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.

Figure 1

Structures of GRP, NMB and Bn-related agonists and antagonists. The entire structures of the different peptides are shown except for GRP which has 27 amino acids and only the COOH terminal 14 amino acids are shown, which is the biologically active end. Both natural occurring agonists and some of the antagonists referred to in the text are shown. Abbreviations. ψ, –CONH peptide bond changed to -CH₂NH- ; pGlu, pyroglutamic acid; Cpa, chlorophenylalanine; NMC, neuromedin C; F₅, pentafluoro-

Figure 2

Ability of the mammalian peptides, gastrin-releasing peptide (GRP) and neuromedin B NMB); the amphibian peptide, bombesin and the synthetic bombesin analogue, [D-Phe⁶, β-Ala¹¹, Phe¹³, Nle¹⁴] bombesin ₆₋₁₄ to interact with the three human classes of bombesin receptors. Data are partially from (Benya et al., 1995b; Ryan et al., 1998b).

Figure 3

Schematic representation of the rat BB₁ receptor showing the postulated transmembrane topology, sites for NH₂-linked glycosylation, possible palmitoylated cysteines in the cytoplasmic tail, and the key amino acids for high affinity NMB interaction (dark) or interaction with the BB₁ receptor specific peptoid antagonist PD 168368 (shaded). Amino acid data is from (Wada et al., 1991), NMB high affinity sites form (Fathi et al., 1993a; Sainz et al., 1998) and the PD 168368 from (Tokita et al., 2001a).

Figure 4

Schematic representation of the murine BB₂ receptor showing the postulated transmembrane topology, sites for NH₂-linked glycosylation, possible palmitoylated cysteines in the cytoplasmic tail, and the key amino acids for high affinity GRP interaction or signaling (dark) or interaction with the BB₂ selective antagonist statin analogue JMV594 or the pseudopeptide analogue JMV641. Amino acid data is from (Spindel et al., 1990; Battey et al., 1991), GRP high affinity sites from (Akeson et al., 1997; Donohue et al., 1999; Lin et al., 2000; Carroll et al., 2000b; Tokita et al., 2002; Glover et al., 2003; Nakagawa et al., 2005) and the JMV594 and JMV641 from (Tokita et al., 2001b).