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Vol. 52, Issue 3, 415-472, September 2000

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

M. de Gasparo1, K. J. Catt, T. Inagami, J. W. Wright and Th. Unger

Novartis Pharma AG, Metabolic & Cardiovascular Diseases, Basel, Switzerland (M.d.G.); Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (K.J.C.); Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee (T.I.); Department of Psychology, Washington State University, Pullman, Washington (J.W.W.); Institute of Pharmacology, Christian-Albrechts-University of Kiel Hospitalstrasse 4, Kiel, Germany (Th.U.)

I. Introduction
    A. Historical Background
    B. International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification Criteria for Classification
    C. Current Nomenclature
    D. Structural Analysis
II. The Type 1 (AT1) Angiotensin Receptor
    A. Angiotensin II Receptors: Early Studies
    B. Cloned AT1 Receptors
    C. Genomic Organization of Rat AT1A and AT1B Receptor Genes
    D. Expression and Regulation of Rat AT1A and AT1B Receptor
    E. The Human AT1 Receptor
        1. AT1 Receptor Gene Polymorphisms and Cardiovascular Disease.
    F. The Amphibian AT1 Receptor
    G. The AT1 Receptor Null Mouse
    H. Structural Basis of Ligand Binding to the AT1 Receptor
        1. Determinants of Ang II Bioactivity.
        2. Agonist Binding Site of the AT1 Receptor.
        3. Antagonist Binding of the AT1 Receptor.
I. AT1 Receptor Signaling Mechanisms
        1. AT1 Receptor Activation and Signal Transduction.
        2. AT1 Receptor and Tyrosine Phosphorylation.
        3. AT1 Receptor-Activated Growth Responses.
        4. Transactivation of Growth Factor Signaling by the AT1 Receptor,
        5. Other AT1 Receptor-Mediated Signaling Pathways.
    J. Receptor Activation and Endocytosis
    K. AT1 Receptor Function in Selected Tissues
        1. The AT1 Receptor and the Brain.
        2. Ang II-Induced Neuronal Signaling Pathways.
        3. Role of Ang III in the Brain.
        4. The AT1 Receptor and the Pituitary Gland.
        5. The AT1 Receptor and the Heart.
III. The Type 2 (AT2) Angiotensin Receptor
    A. Cloning, Purification, and Properties of the AT2 Receptor
    B. Regulation of the AT2 Receptor
    C. AT2 Receptor Diversity
    D. Targeted AT2 Receptor Gene Overexpression and Deletion
        1. Behavioral Changes in AT2 Receptor Null Mice.
    E. Signaling Mechanisms of the AT2 Receptor
        1. Dephosphorylation and Inactivation of the Mitogen-Activated Protein Kinases ERK1 and ERK2.
        2. Activation of Phospholipase A2 and Prostacyclin Generation.
    F. Tissue Distribution of the AT2 Receptor
        1. Brain.
        2. Heart.
        3. Kidney.
        4. Vasculature.
        5. Pancreas, Lung, Thymus, and Other Tissues.
        6. Cells in Primary Culture and Cell Lines Expressing the AT2 Receptor.
    G. Pathophysiological Aspects of AT2 Receptor Activation
        1. The AT2 Receptor Can Induce Apoptosis.
        2. Effects on Vascular Tone.
        3. Vascular Hypertrophy and Fibrosis and the AT2 Receptor.
        4. Renal Tubular Function.
        5. Neuronal Cell Differentiation and Nerve Regeneration.
    H. Summary
IV. The AT4 Receptor
    A. Signaling Mechanisms
    B. Tissue Distribution of the AT4 Receptor
        1. Brain.
        2. Peripheral Tissue.
    C. Development of Agonists and Antagonists
        1. Binding Requirements of AT4 Receptor.
        2. Antagonists of the AT4 Receptor.
    D. Physiology Associated with the AT4 Receptor
        1. Regulation of Blood Flow.
        2. Cardiac Hypertrophy.
        3. Renal Tubular Reabsorption.
        4. Electrophysiological Analysis.
        5. Role of Ang IV in Learning and Memory.
    E. Summary
V. General Conclusions
References

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT1 gene, but two related AT1A and AT1B receptor genes are expressed in rodents. AT1 receptors are predominantly coupled to Gq/11, and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT1-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT2 receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A2, nitric oxide, and cyclic guanosine monophosphate. The AT2 receptor counteracts several of the growth responses initiated by the AT1 and growth factor receptors. The AT4 receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT1 receptors mediate most of the known actions of Ang II, the AT2 receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

1 Address for correspondence: Marc de Gasparo, Novartis Pharma AG, Metabolic & Cardiovascular Diseases, WKL 121-210, P.O. Box 4200, Basel, Switzerland. E-mail: marc.de_gasparo{at}pharma.Novartis.com and m.de_gasparo{at}bluewin.ch (after October 1, 2000)

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Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1313 - C1322.
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 Am. J. Physiol. Cell Physiol.Home page
T. A. Morinelli, J. R. Raymond, A. Baldys, Q. Yang, M.-h. Lee, L. Luttrell, and M. E. Ullian
Identification of a putative nuclear localization sequence within ANG II AT1A receptor associated with nuclear activation
Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1398 - C1408.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. H. Siddiqui and T. Hussain
Enhanced AT1 receptor-mediated vasocontractile response to ANG II in endothelium-denuded aorta of obese Zucker rats
Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1722 - H1727.
[Abstract]