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 (AngII) initiates cellular responses by activation of type I (AT1) and type 2 (AT2) angiotensin receptors. Both AT1 and AT1 receptors have seven transmembrane structures characteristic of G protein-coupled receptors, but only the AT1 receptor undergoes rapid internalization upon agonist binding. In addition to the agonist hormone, the peptide antagonist [Sar1,Ile8]AngII can also induce internalization of the AT1a receptor expressed in mammalian cell lines, but the nonpeptide AT1 receptor blocker losartan does not internalize. AT1 receptor internalization occurs via clathrin-coated pits, but there is evidence that, in contrast to the internalization of other G protein-coupled receptors, the internalization of the AT1 receptor is independent of dynamin and beta-arrestin. Mutagenesis studies demonstrated that AT1 receptor internalization requires two regions in the cytoplasmic tail of the receptor, but it is independent of G protein activation. The dependence of AT1 receptor internalization on the presence of a serine-threonine-rich region suggests that phosphorylation of the receptor tail may regulate the internalization process. The possible role of AT1 receptor internalization in sustained signal generation has been suggested, but its relationship to nuclear AngII receptors is not completely understood.
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PMID:Molecular mechanisms of angiotensin II receptor internalization. 989 40

Arrestins play an important role in regulating desensitization and trafficking of G protein-coupled receptors (GPCRs). However, limited insight into the specificity of arrestin-mediated regulation of GPCRs is currently available. Recently, we used an antisense strategy to reduce arrestin levels in HEK293 cells and characterize the role of arrestins on endogenous G(s)-coupled receptors (Mundell, S. J., Loudon, R. B., and Benovic, J. L. (1999) Biochemistry 38, 8723-8732). Here, we characterized GPCRs coupled to either G(q) (M(1) muscarinic acetylcholine receptor (M(1)AchR) and P2y(1) and P2y(2) purinergic receptors) or G(i) (somatostatin and AT1 angiotensin receptors) in wild type and arrestin antisense HEK293 cells. The agonist-specific desensitization of the M(1)Ach and somatostatin receptors was significantly attenuated in antisense-expressing cells, whereas desensitization of P2y(1) and P2y(2) purinergic and AT1 angiotensin receptors was unaffected by reduced arrestin levels. To further examine arrestin/GPCR specificity, we studied the effects of endogenous GPCR activation on the redistribution of arrestin-2 epitope tagged with the green fluorescent protein (arrestin-2-GFP). These studies revealed a receptor-specific movement of arrestin-2-GFP that mirrored the arrestin-receptor specificity observed in the antisense cells. Thus, agonist-induced activation of endogenous beta(2)-adrenergic, prostaglandin E(2), M(1)Ach, and somatostatin receptors induced arrestin-2-GFP redistribution to early endosomes, whereas P2y(1) and P2y(2) purinergic and AT1 angiotensin receptor activation did not. Thus, endogenous arrestins mediate the regulation of selective G(q)- and G(i)-coupled receptors in HEK293 cells.
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PMID:Selective regulation of endogenous G protein-coupled receptors by arrestins in HEK293 cells. 1077 89

The major mechanism of agonist-induced internalization of G protein-coupled receptors (GPCRs) is beta-arrestin- and dynamin-dependent endocytosis via clathrin-coated vesicles. However, recent reports have suggested that some GPCRs, exemplified by the AT1 angiotensin receptor expressed in human embryonic kidney (HEK) 293 cells, are internalized by a beta-arrestin- and dynamin-independent mechanism, and possibly via a clathrin-independent pathway. In this study, agonist-induced endocytosis of the rat AT1A receptor expressed in Chinese hamster ovary (CHO) cells was abolished by clathrin depletion during treatment with hyperosmotic sucrose and was unaffected by inhibition of endocytosis via caveolae with filipin. In addition, internalized fluorescein-conjugated angiotensin II appeared in endosomes, as demonstrated by colocalization with transferrin. Overexpression of beta-arrestin1(V53D) and beta-arrestin1(1-349) exerted dominant negative inhibitory effects on the endocytosis of radioiodinated angiotensin II in CHO cells. GTPase-deficient (K44A) mutant forms of dynamin-1 and dynamin-2, and a pleckstrin homology domain-mutant (K535A) dynamin-2 with impaired phosphoinositide binding, also inhibited the endocytosis of AT(1) receptors in CHO cells. Similar results were obtained in COS-7 and HEK 293 cells. Confocal microscopy using fluorescein-conjugated angiotensin II showed that overexpression of dynamin-1(K44A) and dynamin-2(K44A) isoforms likewise inhibited agonist-induced AT1 receptor endocytosis in CHO cells. Studies on the angiotensin II concentration-dependence of AT1 receptor endocytosis showed that at higher agonist concentrations its rate constant was reduced and the inhibitory effects of dominant negative dynamin constructs were abolished. These data demonstrate the importance of beta-arrestin- and dynamin-dependent endocytosis of the AT1 receptor via clathrin-coated vesicles at physiological angiotensin II concentrations.
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PMID:Beta-arrestin- and dynamin-dependent endocytosis of the AT1 angiotensin receptor. 1116 Aug 59

Beta-arrestins play a role in AT1 endocytosis by binding the cytoplasmic, C-terminus region T332-S338, the major site of angiotensin II (Ang II)-induced phosphorylation. However, the processes responsible for recruiting beta-arrestin to the activated receptor are poorly defined. In this study, we used CHO-K1 and HEK 293 cells expressing wild-type or mutant AT1 to investigate two possibilities: activated AT1 induces global relocation of beta-arrestins to the plasma membrane or the phosphorylated C-terminus acts as bait to attract beta-arrestins. Results obtained using high osmolarity and dominant-negative beta-arrestin confirmed that internalization of AT1 in both CHO-K1 and HEK 293 cells is predominately via clathrin-mediated endocytosis involving beta-arrestin, and substitution of T332, S335, T336 and S338 with alanine to preclude phosphorylation markedly attenuated AT1 internalization. Confocal microscopy revealed that wild-type AT1 induced a time-dependent translocation of GFP-tagged beta-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did not traffic beta-arrestin 1 at all, and only trafficked beta-arrestin 2 weakly. Results of rescue-type experiments were consistent with the idea that both beta-arrestins are able to interact with the non-phosphorylated receptor, albeit with much lower affinity and beta-arrestin 1 less so than beta-arrestin 2. In conclusion, this study shows that the high affinity binding of beta-arrestins to the phosphorylated C-terminus is the predominant mechanism of agonist-induced beta-arrestin recruitment to the cell surface and AT1 receptor.
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PMID:Agonist-dependent internalization of the angiotensin II type one receptor (AT1): role of C-terminus phosphorylation in recruitment of beta-arrestins. 1517 32

Internalization of a G-protein-coupled receptor (GPCR) is essential to the desensitization, endocytosis, and signal transduction of the receptor. It has been the general view that conventional homologous internalization of a GPCR requires activation of the G-protein(s) coupled to the receptor. However, whether and how GPCR-mediated G-protein-independent signals trigger receptor internalization remains unknown, although G-protein-independent internalization has been reported. Here we show that an angiotensin II (Ang II) type-1 (AT1) receptor mutant incapable of activating any G-protein still undergoes normal internalization. Substitution of Asp125 with Ala and Arg126 with Leu at the highly conserved DRY motif of the AT1 receptor disabled the ability of the receptor to activate G-proteins, as shown by various Ang II binding studies, GDP-GTP exchange, and inositol phosphate production assays. Surprisingly, the mutant internalized normally in the presence of Ang II and transactivated the epidermal growth factor receptor (EGFR). Similar to the wild-type receptor, overexpression of a dominant-negative K220R mutant GRK2 diminished the internalization of D125A-R126L but not the transactivation of EGFR. These data indicate that G-protein-independent specific signals may also trigger homologous internalizations of the AT1 receptor through beta-arrestin-dependent and -independent pathways, suggesting a possible mechanism for G-protein-independent activation of G-protein-coupled receptor kinases (GRKs). This may represent a general mechanism for triggering GPCR internalization.
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PMID:Unconventional homologous internalization of the angiotensin II type-1 receptor induced by G-protein-independent signals. 1599

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
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PMID:Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. 1614 58

Agonist stimulation of G protein-coupled receptors causes receptor activation, phosphorylation, beta-arrestin binding and receptor internalization. Angiotensin II (AngII) causes rapid internalization of the AT1 receptors, whereas AngII-bound AT2 receptors do not internalize. Although the activation of the rat AT1A receptor with AngII causes translocation of beta-arrestin2 to the receptor, no association of this molecule with the AT2 receptor can be detected after AngII treatment with confocal microscopy or bioluminescence resonance energy transfer. These data demonstrate that the two subtypes of angiotensin receptors have different mechanisms of regulation.
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PMID:Differential beta-arrestin binding of AT1 and AT2 angiotensin receptors. 1635 71

The most prevalent physiological effects of ANG II, the main product of the renin-angiotensin system, are mediated by the AT1 receptor, a rhodopsin-like AGPCR. Numerous studies of the cardiovascular effects of synthetic peptide analogs allowed a detailed mapping of ANG II's structural requirements for receptor binding and activation, which were complemented by site-directed mutagenesis studies on the AT1 receptor to investigate the role of its structure in ligand binding, signal transduction, phosphorylation, binding to arrestins, internalization, desensitization, tachyphylaxis, and other properties. The knowledge of the high-resolution structure of rhodopsin allowed homology modeling of the AT1 receptor. The models thus built and mutagenesis data indicate that physiological (agonist binding) or constitutive (mutated receptor) activation may involve different degrees of expansion of the receptor's central cavity. Residues in ANG II structure seem to control these conformational changes and to dictate the type of cytosolic event elicited during the activation. 1) Agonist aromatic residues (Phe8 and Tyr4) favor the coupling to G protein, and 2) absence of these residues can favor a mechanism leading directly to receptor internalization via phosphorylation by specific kinases of the receptor's COOH-terminal Ser and Thr residues, arrestin binding, and clathrin-dependent coated-pit vesicles. On the other hand, the NH2-terminal residues of the agonists ANG II and [Sar1]-ANG II were found to bind by two distinct modes to the AT1 receptor extracellular site flanked by the COOH-terminal segments of the EC-3 loop and the NH2-terminal domain. Since the [Sar1]-ligand is the most potent molecule to trigger tachyphylaxis in AT1 receptors, it was suggested that its corresponding binding mode might be associated with this special condition of receptors.
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PMID:The angiotensin II AT1 receptor structure-activity correlations in the light of rhodopsin structure. 1742 42

The angiotensin II type I (AT(1)) receptor mediates regulation of blood pressure and water-electrolyte balance by Ang II. Substitution of Gly for Asn(111) of the AT(1) receptor constitutively activates the receptor leading to Gq-coupled IP(3) production independent of Ang II binding. The Ang II-activated conformation of the AT1(N111G) receptor was proposed to be similar to that of the wild-type AT(1) receptor, although, various aspects of the Ang II-induced conformation of this constitutively active mutant receptor have not been systematically studied. Here, we provide evidence that the conformation of the active state of the wild-type and the constitutively active AT(1) receptors are different. Upon Ang II binding an activated conformation of the wild-type AT(1) receptor activates G protein and recruits beta-arrestin. In contrast, the agonist-bound AT1(N111G) mutant receptor preferentially couples to Gq and is inadequate in beta-arrestin recruitment.
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PMID:Manifold active-state conformations in GPCRs: agonist-activated constitutively active mutant AT1 receptor preferentially couples to Gq compared to the wild-type AT1 receptor. 1749

From the deep part of the main ligand-binding crevice, a minor, often shallower pocket extends between the extracellular ends of transmembrane domains (TM)-I, II, III and VII of 7TM receptors. This minor binding pocket is defined by a highly conserved kink in TM-II that is induced by a proline residue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric interface between TM-II and TM-VII being of particular significance. Importantly, the minor binding pocket, especially the proline-kink in TM-II, is involved in G protein versus arrestin pathway-biased signaling, for example in the angiotensin AT1 system. Consequently, this pocket could be specifically targeted in the development of functionally biased drugs.
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PMID:The minor binding pocket: a major player in 7TM receptor activation. 2087 Mar


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