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Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
Abstract
Abstract I. A Short History of Kinins and Their Receptors II. Pharmacological Classification of Kinin Receptor Subtypes A. Peptide Agonists B. Peptide Antagonists C. Nonpeptide Ligands 1. B2 Receptor Agonists. 2. B2 Receptor Antagonists. 3. B1 Receptor Antagonists. III. Structural Aspects of Kinin Receptors and Their Genes A. Organization and Structure of the Receptor Genes B. Receptors and Their Post-Translational Modifications 1. Glycosylation. 2. Disulfide Bridging. 3. Acylation. 4. Phosphorylation. C. Agonist and Antagonist Binding Sites in the Receptors 1. B2 Receptor Agonists. 2. B2 Receptor Antagonists. 3. B1 Receptor Agonists. 4. B1 Receptor Antagonists. D. Evolutionary Aspects of Kinin Receptors IV. Molecular and Cellular Aspects of Kinin Receptor Signaling and Regulation A. Agonist-Dependent and -Independent Mechanisms of Receptor Activation B. Receptor Cellular Signaling Pathways C. Protein-Protein Interactions in Receptor Signaling D. Receptor Desensitization E. Cellular Distribution and Trafficking of Receptors V. Long-Term Regulation of Kinin Receptors by Proinflammatory Factors A. Postisolation Induction of the B1 Receptor B. Proinflammatory Cytokines and Growth Factors C. Agonists D. Ras and B2 Receptors E. Regulatory Elements in the Gene Promoters F. mRNA Stability VI. Distribution and Pathophysiological Function of Kinin Receptors A. Circulation and Renal Function B. Inflammation C. Pain and Neurology D. Diabetes VII. Kinin Receptors and Human Disease A. Cardiovascular Disease 1. Left Ventricular Hypertrophy and Cardiomyopathy. 2. Vascular Tone. 3. Hypertension. B. Renal Disease C. Airway Disease D. Neurological Disease E. Cancer F. Other Disease States G. Caveats VIII. Kinin Receptors and Drug Development A. Pain B. Cardiovascular Function C. Airway Function D. Cancer IX. Epilogue
Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B1 receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1
. Both receptors act through G
q to stimulate phospholipase C followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through Gi to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
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