The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-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 AT(2) 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 A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) 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 AT(1) receptors mediate most of the known actions of Ang II, the AT(2) 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.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Angiotensin II elicits different responses which affect cardiovascular, neuronal and electrolyte transport regulation. To understand the mechanisms responsible for its various actions, the receptor for angiotensin II has long been sought, but numerous attempts to purify the receptor have been unsuccessful owing to its instability and low concentration. We report here the expression cloning of a complementary DNA encoding a bovine angiotensin II receptor to overcome these difficulties. The receptor cDNA encodes a protein of 359 amino-acid residues with a transmembrane topology similar to that of other G protein-coupled receptors. COS-7 cells transfected with the cDNA expressed specific and high-affinity binding sites for angiotensin II, angiotensin II antagonist and a non-peptide specific antagonist for type-1 receptor. Dithiothreitol inhibited ligand binding. The concentration of intracellular Ca2+ and of inositol-1,4,5-trisphosphate increased in the transfected COS-7 cells in response to angiotensin II or angiotensin III, indicating that this receptor is the type-1 receptor for angiotensin II. Northern blot analysis revealed that the messenger RNA for this receptor is expressed in bovine adrenal medulla, cortex and kidney.

Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor

G-protein-coupled receptor dimerization: modulation of receptor function

Protein-protein interactions are involved in the regulation of a large number of biological processes. It is well established that a variety of cell surface receptors interact with each other to form dimers, and that this is essential for their activation. Although the existence of G protein coupled receptor dimers was predicted from early pharmacological and biochemical analysis, solid evidence supporting dimerization has come within the past few years following the cloning of G protein coupled receptor cDNAs. Using differential epitope tagging and selective immunoisolation of receptor complexes, dimerization of a number of G protein coupled receptors including members of the rhodopsin, secretin, and metabotropic glutamate receptor families have been reported. More recently fluorescence or bioluminescence resonance energy transfer techniques have been used to examine dimerization of these receptors in live cells. These studies have found that whereas in some cases there is an agonist induced increase in the level of dimers, in others there is a decrease or no change in dimer levels. Several recent studies have also reported the ability of related members of G protein coupled receptors to heterodimerize. These heterodimers exhibit distinct physical and functional properties. Examination of possible sites of interactions between receptors has implicated a role for extracellular, transmembrane and/or C-terminal region in dimerization. The functional consequences of dimerization, explored mainly using mutant receptors, have demonstrated a role in modulating agonist affinity, efficacy, and/or trafficking properties. Thus dimerization appears to be a universal phenomenon that provides an additional mechanism for modulation of receptor function as well as cross-talk between G protein coupled receptors.

G protein coupled receptor dimerization: implications in modulating receptor function.

I. Introduction THE synthesis and secretion of aldosterone by adrenal glomerulosa cells is under the control of three major stimulatory extracellular messengers: angiotensin II (Ang II), extracellular potassium (K+), and ACTH (1, 2). Although in certain species PTH (3), vasopressin (4, 5), and acetylcholine (6) also enhance the aldosterone secretory response, the universal physiological role of these agonists in vivo is not yet clear. In addition to stimulatory extracellular messengers, several hormones exert inhibitory effects. The most prominent of these is atrial natriuretic peptide (ANP), but in some species both dopamine and somatostatin also cause inhibition (7–9). The present discussion will focus on the role of calcium (Ca2+) in the acute (hours vs. days) regulation of aldosterone secretion by Ang II. Two traditional signaling pathways have been identified in the glomerulosa cell. The first is the stimulation of adenylate cyclase activity with the consequent production of cAMP and the activation o...

Role of calcium in angiotensin II-mediated aldosterone secretion.

Specific receptor sites for angiotensin II (All) were analyzed in the adrenal cortex and other target tissues including liver, anterior pituitary gland, and smooth muscle, after covalent labeling with the radioactive photoaffinity analog 125l-[Sar1,(4-N3)Phe8]-All. The photoreactive All derivative retained high affinity for adrenal receptors and full steroidogenic activity in adrenal glomerulosa cells. In bovine adrenal cortex, covalent labeling of All receptors by the photoreactive analog was specifically inhibited by [Sar1]All with an IC50 of about 5 nm. The Mr of the covalent All-receptor complex during polyacrylamide gel electrophoresis of the labeled protein under reducing conditions was 58,000. Under nonreducing conditions, a minor band with Mr of 105,000 was also observed. Two labeled species were also found during gel permeation chromatography of the detergent-solubilized complex, with Mrs of 64,000 and 86,000. The pl of the solubilized photolabeled complex was absorbed to wheat germ lectin Sephar...

/pdf/physicochemical-characterization-of-photoaffinity-labeled-n5lejpoy52.pdf

Catherine M. Leach Harper

Papers

Physicochemical Characterization of Photoaffinity-Labeled Angiotensin II Receptors