Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) receptors, estimated by the specific binding of the peptide Ang II receptor antagonist [125I] [Sar1,Ile8]Ang II, are localized on multiple ovarian structures, including follicular granulosa cells. Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor. To understand the function of Ang II in ovarian follicles, we compared the biochemical properties and transmembrane signaling pathways of the granulosa cell AT2 receptor with those properties generally associated with Ang II receptors found in the adrenal zona glomerulosa, where the AT1 receptor predominates. The mol wt of the granulosa cell AT2 receptor (approximately 79,000), estimated by affinity cross-linking studies, is similar to that of the adrenal zona glomerulosa Ang II receptor. Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM). However, unlike the adrenal zona glomerulosa Ang II receptor, the granulosa cell AT2 receptor does not undergo agonist-induced endocytosis. Further, Ang II does not affect basal or stimulated inositol phosphate production, intracellular Ca2+ mobilization, or adenylyl cyclase or guanylyl cyclase activity in granulosa cells. The granulosa cell AT2 receptor does not appear to directly interact with guanine nucleotide binding regulatory proteins, since agonist dissociation from the AT2 receptor is unaffected by the GTP analog guanosine 5'-O-(3-thiotriphosphate); in contrast, the AT1 receptor appears to directly interact with guanine nucleotide binding regulatory protein, because agonist dissociation from the AT1 receptor is stimulated by guanosine 5'-O-(3-thiotriphosphate). These studies clearly demonstrate that the granulosa cell AT2 receptor is functionally distinct from the well characterized adrenal zona glomerulosa Ang II receptor. The exclusive presence of the AT2 receptor on the granulosa cell makes it an ideal cell type for studying the potential, but as yet unknown, function of this receptor.
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PMID:Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. 184 6

The purpose of recent studies was to investigate the expression of angiotensin II (Ang II) receptor sites in afferent arterioles freshly isolated from the rat kidney, and the role of Ang II on renin release by these vessels. The method of isolation and purification of renal microvessels was based on iron oxide infusion into the kidneys and separation of the afferent arterioles from glomeruli and connective tissue with the aid of a magnetic field, successive passages through various sieves, and harvesting with collagenase. Ang II receptor characteristics were evaluated by radioligand binding studies using the non-peptide Ang II antagonists of AT1 (Dup-753 and -532) and AT2 (PD-123319 and CGP-42112) receptors. AT1 antagonists displaced up to 80% of the Ang II binding with high affinity (3 nM), whereas the remaining 20% showed low affinity for the Dup compounds and CGP-42112 (> 10 microM), and intermediate affinity for PD-123319 (12 microM). These data suggest the existence of two Ang II receptor subtypes in the renal vasculature of the rat. In separate experiments, renin release by isolated afferent arterioles in vitro was 9 ng/hr/mg under control conditions. Ang II (0.1 microM) inhibited renin secretion by 20%, whereas the adenylyl cyclase activator forskolin (10 microM) stimulated renin secretion by 50%. In arterioles isolated from rats chronically treated with a converting enzyme inhibitor (perindoprilate) to reduce endogenous formation of Ang II, renin release increased 20-fold under control conditions in vitro and was further stimulated by forskolin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II receptors and renin release in rat glomerular afferent arterioles. 770 9

To identify the mechanisms of action of isoforms angiotensin II receptors (AT1A, AT1B, and AT2) and to overcome the difficulties encountered in attempts to purify the receptors, we have expression-cloned their cDNAs from bovine and rat sources and isolated human cDNA and rat and human genomic DNA. The AT1A and AT1B cDNAs were found to encode respective receptor proteins with 359 amino acid residues, whereas, AT2 encodes a 363 amino acid residue receptor protein. Both AT1 and AT2 were found to conform with the seven transmembrane receptor structural motif, but showed only 32% amino acid residue identity to each other. The AT1 receptor was shown to be coupled to, at least, three different G proteins activating phospholipase C, inhibiting adenylyl cyclase and opening an L-type Ca(2+)-channel, whereas, AT2 was found to inhibit a phosphotyrosine phosphatase activity without affecting guanylyl cyclase by a pertussis-toxin-sensitive, presumably G-protein-mediated mechanism.
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PMID:Angiotensin II receptors: cloning and expression. 774 65

We have previously shown that the human adrenocortical H295R cell line expresses the type 1 angiotensin II receptor (AT1-R) and that expression of this receptor is downregulated at the level of mRNA by forskolin or dibutyryl-cAMP as well as by angiotensin II (Ang II). In this study we examine the effects of K+ on both AT1-R mRNA and receptors, as monitored through 125I-Ang II binding in the presence of PD 123319. After treatment with a maximal stimulatory steroidogenic dose of K+ (14 mmol/L), H295R cells showed an increase in cytosolic free Ca2+ from 113 to 212 nmol/L. Unlike the effects of Ang II, this increase could be abolished by pretreatment with the Ca2+ channel antagonist nifedipine (1 mumol/L). AT1-R mRNA levels also fell in response to elevated extracellular K+ in a dose-dependent (Kd, 9 mmol/L; maximal fall in message at 12 mmol/L) and time-dependent (maximum 50% at 12 hours) manner. The change in AT1-R mRNA level was less rapid than that in response to activation of phosphoinositidase C by Ang II or adenylyl cyclase by forskolin or by dibutyryl-cAMP. Unlike the action of Ang II but similar to the action of forskolin or dibutyryl-cAMP, the action of K+ was sustained. Changes in mRNA level in response to treatment with K+, Ang II, or dibutyryl-cAMP were also paralleled by changes in 125I-Ang II binding in each case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potassium negatively regulates angiotensin II type 1 receptor expression in human adrenocortical H295R cells. 776 52

Angiotensin II has been reported to stimulate the proximal tubule Na-H antiporter by inhibition of adenylyl cyclase, and possibly by an adenosine 3',5'-cyclic monophosphate (cAMP)-independent mechanism. We examined the effect of angiotensin II on Na-H antiporter activity (JNa-H) in opossum kidney (OKP) cells, a proximal tubule-like cell line, whose Na-H antiporter resembles that of the proximal tubule apical membrane. We found that angiotensin II regulates JNa-H in a concentration-dependent manner similar to the proximal tubule, with angiotensin II concentrations < 10(-8) M stimulating and > 10(-8) M inhibiting JNa-H. The stimulatory effect of angiotensin II was blocked by 10(-8) M losartan and was pertussis toxin sensitive, suggesting mediation through an angiotensin II (AT1) receptor coupled to a pertussis toxin-sensitive G protein. Acute treatment with 10(-4) M 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) inhibited JNa-H by 30% and blocked angiotensin II-induced stimulation. However, angiotensin II (10(-12)-10(-6) M) did not inhibit basal, dopamine-stimulated, or forskolin-stimulated cAMP production measured in the presence of 3-isobutyl-1-methylxanthine (IBMX). In addition, angiotensin II had no effect on cAMP levels measured in the absence of IBMX. We conclude that angiotensin II at physiological concentrations stimulates JNa-H in OKP cells via a cAMP-independent mechanism mediated by an AT1 receptor and a pertussis toxin-sensitive G protein.
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PMID:Angiotensin II stimulation of Na-H antiporter activity is cAMP independent in OKP cells. 802 91

Recent evidence suggests that there are two classes of receptors for angiotensin II (AngII), AT1 which is sensitive to losartan (DuP753) and is G-protein coupled, and AT2 which is sensitive to both PD123319 and CGP42112A, and is non-G-protein coupled. In rat mesangial cells two subtypes of AT1 receptor could be distinguished, AT1A subtype is more sensitive to losartan whereas AT1B subtype is more sensitive to PD123319, but insensitive to CGP42112A. The present studies were designed to ascertain which receptor subtype mediates three AngII-induced physiologic functions in rat mesangial cells namely intracellular Ca2+ mobilization, adenylyl cyclase inhibition and protein synthesis as monitored via [3H]leucine incorporation. The rank order of potency for inhibition of AngII-induced [Ca(2+)]i mobilization and adenylyl cyclase regulation was PD123319 > or = losartan > CGP42112A. By contrast, losartan was quite effective at inhibiting protein synthesis (IC50 = 8 nM) while PD123319 was without effect. These findings are consistent with AngII mediated signal transduction through AT1A and AT1B sites for phospholipase C mediated [Ca(2+)]i mobilization and inhibition of adenylyl cyclase. On the other hand, AT1A receptors appear to exclusively mediate AngII-induced protein synthesis. These observations underscore the complexity of AngII mediated signal transduction in glomerular mesangium.
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PMID:Signal transduction mediated by angiotensin II receptor subtypes expressed in rat renal mesangial cells. 846 70

The peptide hormones angiotensin II and vasopressin play a major role in water and electrolyte homeostasis. These peptides act on membrane bound receptors, which all belong to the large family of G protein coupled receptors. The receptors for angiotensin II are divided into 2 groups: the AT1 receptors, which are responsible for transducing the majority if not all actions of angiotensin II. The primary structure of this receptor has been identified by molecular cloning of the cDNA in many species and is represented by two isoforms (AT1A and AT1B) in rodent. This receptor is specifically coupled to a G protein of the Gq family, which activates a phospholipase C producing two second messengers involved in protein phosphorylation and calcium mobilization. The sequences or amino-acids involved in the binding site of peptidic agonists or non peptidic antagonists and in receptor activation and G protein coupling have been identified; the AT2 receptor primary sequence has also been identified, but the physiological role and the signaling mechanisms of this receptor are still unknown. The vasopressin receptors can be divided in three classes depending on their pharmacological properties, their tissular distribution and their coupling mechanisms. The primary structure of all 3 types of receptors has been elucidated. The V1a receptor is ubiquitous and transduces the vasoconstrictive effect of vasopressin by activating a phospholipase C, like the AT1 receptors; the V2 receptor is involved in water reabsorption in the kidney and is coupled to a GS protein activating an adenylyl cyclase; the V3 or V1b receptor is expressed in the pituitary, where it regulates the ACTH secretion, via the activation of a phospholipase C. These two family of G protein coupled receptors illustrate the structural and functional diversity of the receptors for peptidic hormones.
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PMID:[Comparative study of the structure and molecular functions of angiotensin II and vasopressin receptors]. 859 Feb 17

To understand the molecular mechanism by which the angiotensin II (AII) type 1 receptor (AT1 receptor) transduces its biological signal, we examined the role of various signaling molecules involved in AT1 receptor signaling in Chinese hamster ovary cells stably transfected with the AT1 receptor. AT1 receptor-transfected cells responded to AII treatment by inhibiting adenylyl cyclase, increasing the intracellular Ca2+ concentration, and activating protein kinase C (PKC) alpha and PKC epsilon. AII also activated the c-fos gene and mitogen-activated protein (MAP) kinases. The activation of PKC, the c-fos gene, and MAP kinases was blocked by inhibition of PKC induced by pretreatment with 12-O-tetradecanoylphorbol-13-acetate but not by pretreatment with pertussis toxin, suggesting that PKC couples to the activation of the the c-fos gene and MAP kinases. In addition, AII activated Raf-1 and MAP kinase kinase in a PKC-dependent manner. A dominant negative mutant of Ras had no effect on AII-induced MAP kinase or c-fos gene activation. Thus, the AT1 receptor signals through Raf-1 and its downstream signaling molecules by a PKC-dependent mechanism that does not involve Ras activation.
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PMID:Angiotensin II type 1 receptor signals through Raf-1 by a protein kinase C-dependent, Ras-independent mechanism. 879 90

Experiments in inbred strains of normotensive and hypertensive rats have clearly demonstrated circadian rhythms in blood pressure and heart rate. Pre- and postsynaptic signal transduction processes in vitro can, but need not, vary with circadian time, greatly depending on the strain of rats investigated. These data highlight the notion of a strain-dependent, and thus genetic, regulation of the cardiovascular system. Obviously, circadian rhythms in blood pressure cannot be explained by single biochemical parameters, but results from both in vitro and in vivo studies give first evidence that the vascular nitric oxide-cGMP system may be involved in the circadian regulation of blood pressure in WKY and SHR rats. In secondary hypertensive TGR and in their normotensive controls, SPRD, the guanylyl cyclase system does not seem to play a role in circadian blood pressure regulation. In neither of the four strains studied did aortic adenylyl cyclase show any time-dependent variation. Because vascular tissue was taken from the thoracic aorta of the rats, a contribution of adenylyl cyclase to circadian blood pressure regulation in small resistance arteries cannot be ruled out. Further studies in different parts of the vascular tree are needed to definitely answer that question. No data are available on time-dependent variation in the activity of phospholipase C, the second messenger pathway of vascular alpha-adrenoceptors and angiotensin II AT1-receptors, both of which mediate vasoconstriction. Future research into this system will be helpful in identifying mechanisms involved in blood pressure regulation in SPRD and TGR.
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PMID:Signal transduction in animal models of normotension and hypertension. 885 34

The regulation of the AT1 receptor gene was studied in neonatal cardiomyocytes and fibroblasts in vitro. Incubation with angiotensin II (Ang II) resulted in a time-dependent and dose-dependent decrease in AT1 mRNA levels in both cardiomyocytes and fibroblasts. Coincubation with Ang II and the specific AT1 antagonist losartan prevented the decrease in AT1 mRNA whereas the AT2 antagonist PD123319 was ineffective in preventing the decrease in AT1 mRNA. Because Ang II is known to decrease cAMP levels in cardiomyocytes, the role of cAMP in the regulation of the AT1 gene was examined. Treatment with the adenylyl cyclase stimulant forskolin or the cAMP stereoisomer Sp-cAMPS increased AT1 mRNA levels or prevented the Ang II mediated decrease in AT1 mRNA levels. The role of calcium in the regulation of the AT1 gene was determined by incubation with the calcium ionophores A23187 and ionomycin (0.0625-1 microM) which resulted in a profound, dose-dependent decrease in AT1 mRNA levels. Treatment with BAPTA, an intracellular chelator of calcium, prevented the Ang II-mediated decrease in AT1 mRNA. Therefore Ang II is a potent negative regulator of the AT1 gene in cardiomyocytes and fibroblasts via the AT1 receptor. This Ang II mediated decrease in AT1 mRNA is mediated by two complementary mechanisms involving cAMP and intracellular calcium.
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PMID:AT1 receptor gene regulation in cardiac myocytes and fibroblasts. 887 82


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