Constitutive Activation of the Angiotensin II Type 1 Receptor Alters the Spatial Proximity of Transmembrane 7 to the Ligand-binding Pocket

Boucard, Antony A.; Roy, Marise; Beaulieu, Marie-Ève; Lavigne, Pierre; Escher, Emanuel; Guillemette, Gaétan; Leduc, Richard

doi:10.1074/jbc.m305952200

Cited by 54 publications

(74 citation statements)

References 39 publications

(43 reference statements)

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“…7 However, TM7 shifts away from the ligand-binding pocket in the AT 1 -N111G receptor, 10 implying that the conformation of AT 1 receptor during stretch-induced activation is different from that of the constitutively active AT 1 receptor. In general, GPCRs are structurally flexible and unstable, and multiple conformational states exist during the GPCR activation process.…”

Section: Discussionmentioning

confidence: 99%

“…9 However, studies using substituted cysteine accessibility mapping (SCAM) showed that conformation of the AT 1 p-ERKs during stretch-induced activation is quite different from that of the AT 1 -N111G receptor. 7,10 Transmembrane domain 7 (TM7) of the AT 1 receptor undergoes a counterclockwise rotation and a shift toward the ligand-binding pocket in response to mechanical stretch, 7 but it shifts away from the ligand-binding pocket in the AT 1 -N111G receptor. 10 In this study, we show that, as an inverse agonist, olmesartan strongly inhibits the stretch-induced activation of the AT 1 receptor, as well as the constitutive activity of the AT 1 -N111G receptor.…”

Section: Introductionmentioning

confidence: 99%

“…7,10 Transmembrane domain 7 (TM7) of the AT 1 receptor undergoes a counterclockwise rotation and a shift toward the ligand-binding pocket in response to mechanical stretch, 7 but it shifts away from the ligand-binding pocket in the AT 1 -N111G receptor. 10 In this study, we show that, as an inverse agonist, olmesartan strongly inhibits the stretch-induced activation of the AT 1 receptor, as well as the constitutive activity of the AT 1 -N111G receptor. In addition to the ternary interactions involving the hydroxyl group and the carboxyl group of the imidazole ring of olmesartan, a specific drugreceptor interaction between the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor is also important for the potent inverse agonist activity olmesartan exerts against stretch-induced AT 1 receptor activation.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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“…Although using SCAM to probe receptor structure has its shortcomings, the method has been applied to a number of GPCRs, including D2 dopamine receptor, A1 adenosine receptor and AT1 angiotensin II receptors [for example, (5,13,(54)(55)(56)], for which no X-ray crystal structures are available. Coupled with rhodopsin-based molecular modeling, SCAM analysis has proven to be very useful for elucidating the structures of GPCRs.…”

Section: Limitations Of Scammentioning

confidence: 99%

The Seventh Transmembrane Domains of the δ and κ Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions

Campillo

Pardo

et al. 2005

Biochemistry

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We applied the substituted cysteine accessibility method (SCAM) to map the residues of the transmembrane helices (TMs) 7 of δ and κ opioid receptors (δOR and κOR) that are on wateraccessible surface of the binding-site crevices. Twenty five consecutive residues (except C7.38) in the TMs7 were mutated to Cys, one at a time, and each mutant was expressed in HEK 293 cells. Most mutants displayed similar binding affinity for [ 3 H]diprenorphine, an antagonist, as the wildtypes. Pretreatment with (2-aminoethyl) methanethiosulfonate (MTSEA) inhibited [ 3 H] diprenorphine binding to eight δOR and eight κOR mutants. All mutants except δOR L7.52(317)C were protected by naloxone from MTSEA effect, indicating that the side chains of V7.31(296), A7.34 (299), I7.39(304), L7.41(306), G7.42(307), P7.50(315) and Y7.53(318) of δOR and S7.34(311), F7.37(314), I7.39(316), A7.40(317), L7.41(318), G7.42(319), Y7.43(320) and N7.49(326) of κOR are on water-accessible surface of the binding pockets. Combining the SCAM data with rhodopsinbased molecular models of the receptors led to the following conclusions. i) The residues of the extracellular portion of TM7 predicted to face TM1 are sensitive to MTSEA in κOR, but are not in δOR. Thus, TM1 may be closer to TM7 in δOR than in κOR. ii) MTSEA-sensitive mutants start at position 7.31(296) in δOR and at 7.34(311) in κOR, suggesting that TM7 in δOR may have an additional helical turn (from 7.30 to 7.33). iii) There is a conserved H-bond network linking D2.50 of the NLxxxD motif in TM2 with W6.48 of the CWxP motif in TM6. iv) The NPxxY motif in TM7 interacts with TM2, TM6, and helix 8 to maintain receptors in inactive states. To the best of our knowledge, this represents the first such comparison of the structures of two highly homologous GPCRs.More than one thousand G protein-coupled receptors (GPCRs) are present in the human genome. GPCRs play important roles in physiological functions, including smell, taste, light perception, neurotransmission, functions of endocrine and exocrine glands and immune functions. In addition, GPCRs are targets of numerous clinically used drugs. It is, therefore, of great interests to understand their structures at the molecular level. Based on structural characteristics, GPCRs are classified into multiple families and the rhodopsin family is by far the largest in number. To date, rhodopsin is the only GPCR of which high-resolution crystal *Address correspondence to: Dr. Lee-Yuan Liu-Chen, Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA 19140, phone: (215) 707−4188; fax: (215) 707−7068; e-mail: E-mail: lliuche@temple.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2009 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript structures have been elucidated (1-3). Rhodopsin has an extracellular N-terminal domain, seven transmembrane helices (TMs) connected by alternating intracellular and extracellular hydrophilic loops and an in...

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“…As reported previously (26), the various concentrations of MTSEA had very little effect (no more than a 20% reduction at high MTSEA concentrations) on the binding properties of the wild-type AT 1 receptor, which contains 10 endogenous cysteines (Fig. 1).…”

Section: F170cmentioning

confidence: 55%

Analysis of Transmembrane Domains 1 and 4 of the Human Angiotensin II AT1 Receptor by Cysteine-scanning Mutagenesis

Yan

Holleran

Lavigne³

et al. 2010

Journal of Biological Chemistry

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The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the AT 1 receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT 1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. Here, we investigated the role of the first and fourth transmembrane domains (TMDs) in the formation of the binding pocket of the human AT 1 receptor using the substituted-cysteine accessibility method. Each residue within the Phe-28( The octapeptide hormone angiotensin II (AngII) 4 is the active component of the renin-angiotensin system. It exerts a wide variety of physiological effects, including vascular contraction, aldosterone secretion, neuronal activation, and cardiovascular cell growth and proliferation (1, 2). Virtually all the known physiological effects of AngII are produced through the activation of the AT 1 receptor, which belongs to the G proteincoupled receptor (GPCR) superfamily (3, 4). The AT 1 receptor belongs to the rhodopsin-like family A of G protein-coupled receptors, which have a seven-transmembrane helix structure, an extracellular N-terminal tail, an intracellular C-terminal domain, and three extracellular and three intracellular loops.The seven transmembrane domains (TMDs) of GPCRs constitute structural support for signal transduction. Like other family A GPCRs such as rhodopsin and adrenergic receptors, the AT 1 receptor undergoes spontaneous isomerization between its inactive state and its active state (5). Movement of TMD helices through translational or rotational displacement is believed to be essential to achieve the active state (6 -8). These conformational changes would sustain GTP/GDP exchange on specific guanine nucleotide-binding proteins (G proteins) leading to activation of intracellular signaling cascades (5). For the AT 1 receptor, it has been proposed that TMD3, TMD5, TMD6, and TMD7 may participate in the activation process by providing a network of interactions throughout the AngII-binding pocket (9). The dynamics of this network would require that, following agonist binding, novel or existing interactions between the TMDs would either be created or broken, respectively.Based on homology with the recent high resolution structures of the ␤1 adrenergic, ␤2 adrenergic, and A 2A adenosine receptors (10 -12) it was expected that the binding site of the AT 1 receptor would be formed between its seven, mostly hydrophobic transmembrane domains and would be accessible to charged water-soluble agonists, like AngII. For this receptor, the binding site would thus be contained within a hydrophilic crevice, the binding pocket, extending from the extracellular surface of the receptor to the transmembrane portions. Because all crystallized structures to date suggest that TMD1 and TMD4 are somewhat removed from the binding pocket (13) The substituted-cysteine accessibility method (SCAM) (20 -22) is an ingenious ap...

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Constitutive Activation of the Angiotensin II Type 1 Receptor Alters the Spatial Proximity of Transmembrane 7 to the Ligand-binding Pocket

Cited by 54 publications

References 39 publications

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

The Seventh Transmembrane Domains of the δ and κ Opioid Receptors Have Different Accessibility Patterns and Interhelical Interactions

Analysis of Transmembrane Domains 1 and 4 of the Human Angiotensin II AT1 Receptor by Cysteine-scanning Mutagenesis

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