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Article

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

Digestive Diseases Branch, National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (R.T.J.); Office of the Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (J.F.B.); Division of Neuroscience, Oregon Primate Research Center, Beaverton, Oregon (E.R.S.); and Division of Medicine and Pharmacology, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), Chicago, Illinois (R.V.B.)

Abstract

I. Introduction

II. Molecular Basis for Nomenclature

III. BB1 Receptor

A. Early Studies of the BB1 Receptor

B. Cloned BB1 Receptor and Receptor Structure

C. BB1 Receptor Genomic Organization

D. BB1 Receptor Expression

E. BB1 Receptor Pharmacology

1. BB1 Receptor Agonists.

2. BB1 Receptor Antagonists.

F. BB1 Receptor Structural Basis of Receptor Binding/Activation

1. BB1 Receptor Agonist Binding/Activation.

2. BB1 Receptor Antagonist Binding.

G. BB1 Receptor Signaling, Activation, and Modulatory Processes (Internalization, Down-Regulation, and Desensitization)

H. BB1 Receptor Function in Various Tissues and in Vivo

I. BB1 Receptor in Diseases

IV. BB2 Receptor

A. Early Studies of the BB2 Receptor

B. Cloned BB2 Receptor and Receptor Structure

C. BB2 Receptor Genomic Organization

D. BB2 Receptor Expression

E. BB2 Receptor Pharmacology

1. BB2 Receptor Agonists.

2. BB2 Receptor Antagonists, Partial Agonists, and Biased Agonists.

a. BB2 receptor antagonists.

b. BB2 receptor partial agonists.

c. BB2 receptor-biased agonists.

F. BB2 Receptor Structural Basis of Receptor Binding/Activation

1. BB2 Receptor Agonist Binding/Activation.

2. BB2 Receptor Antagonist Binding.

G. BB2 Receptor Signaling, Activation, and Modulatory Processes (Internalization, Down-Regulation, and Desensitization)

H. BB2 Receptor Function in Various Tissues and in Vivo

I. BB2 Receptor in Diseases

V. BB3 Receptor

A. Early Studies of the BB3 Receptor

B. Cloned BB3 Receptor and Receptor Structure

C. BB3 Receptor Genomic Organization

D. BB3 Receptor Expression

E. BB3 Receptor Pharmacology

1. BB3 Receptor Agonists.

2. BB3 Receptor Antagonists.

F. BB3 Receptor Structural Basis of Receptor Binding/Activation

1. BB3 Receptor Agonist Binding/Activation.

2. BB3 Receptor Antagonist Binding.

G. BB3 Receptor Signaling, Activation, and Modulatory Processes (Internalization, Down-Regulation, and Desensitization)

H. BB3 Receptor Function in Various Tissues and in Vivo

I. BB3 Receptor in Diseases

VI. Therapeutic Implications of Bombesin Receptors

VII. Unresolved Nomenclature Issues

The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB₁), the gastrin-releasing peptide (GRP) receptor (BB₂), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB₃). 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 BB₃ 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.