β1‐, β2‐ and atypical β‐adrenoceptor‐mediated relaxation in rat isolated aorta

Brawley, L; Shaw, Angus M.; MacDonald, Allan

doi:10.1038/sj.bjp.0703091

Cited by 58 publications

(41 citation statements)

References 33 publications

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“…Furthermore, both β 1 - and β 2 -AR subtypes contributed to this response, the β 2 subtype being predominant according to the efficiency of the selective β 1 - and β 2 -AR antagonists to inhibit this response. This is consistent with the fact that both β 1 - and β 2 -AR are localized at the SMC membrane and contribute to the β-adrenergic relaxation in rat aorta [38], [39]. This also indicates that our culture protocol maintains the expression of these receptors [40].…”

Section: Discussionsupporting

confidence: 89%

β-Adrenergic cAMP Signals Are Predominantly Regulated by Phosphodiesterase Type 4 in Cultured Adult Rat Aortic Smooth Muscle Cells

et al. 2012

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BackgroundWe investigated the role of cyclic nucleotide phosphodiesterases (PDEs) in the spatiotemporal control of intracellular cAMP concentrations in rat aortic smooth muscle cells (RASMCs).Methodology/Principal FindingsThe rank order of PDE families contributing to global cAMP-PDE activity was PDE4> PDE3 = PDE1. PDE7 mRNA expression but not activity was confirmed. The Fluorescence Resonance Energy Transfer (FRET)-based cAMP sensor, Epac1-camps, was used to monitor the time course of cytosolic cAMP changes. A pulse application of the β-adrenoceptor (β-AR) agonist isoproterenol (Iso) induced a transient FRET signal. Both β1- and β2-AR antagonists decreased the signal amplitude without affecting its kinetics. The non-selective PDE inhibitor (IBMX) dramatically increased the amplitude and delayed the recovery phase of Iso response, in agreement with a role of PDEs in degrading cAMP produced by Iso. Whereas PDE1, PDE3 and PDE7 blockades [with MIMX, cilostamide (Cil) and BRL 50481 (BRL), respectively] had no or minor effect on Iso response, PDE4 inhibition [with Ro-20-1724 (Ro)] strongly increased its amplitude and delayed its recovery. When Ro was applied concomitantly with MIMX or Cil (but not with BRL), the Iso response was drastically further prolonged. PDE4 inhibition similarly prolonged both β1- and β2-AR-mediated responses. When a membrane-targeted FRET sensor was used, PDE3 and PDE4 acted in a synergistic manner to hydrolyze the submembrane cAMP produced either at baseline or after β-AR stimulation.Conclusion/SignificanceOur study underlines the importance of cAMP-PDEs in the dynamic control of intracellular cAMP signals in RASMCs, and demonstrates the prominent role of PDE4 in limiting β-AR responses. PDE4 inhibition unmasks an effect of PDE1 and PDE3 on cytosolic cAMP hydrolyzis, and acts synergistically with PDE3 inhibition at the submembrane compartment. This suggests that mixed PDE4/PDE1 or PDE4/PDE3 inhibitors would be attractive to potentiate cAMP-related functions in vascular cells.

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Section: Discussionsupporting

confidence: 89%

β-Adrenergic cAMP Signals Are Predominantly Regulated by Phosphodiesterase Type 4 in Cultured Adult Rat Aortic Smooth Muscle Cells

et al. 2012

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“…The expression of mRNA and protein of the ␤ 3 -AR was recently demonstrated in rat aortic endothelial cells (Rautureau et al, 2002). The presence of a functional ␤-AR, presenting more pharmacological similarities with the atypical ␤-AR than with the ␤ 3 -AR, was also reported in rat aorta (Shafiei and Mahmoudian, 1999;Brawley et al, 2000). However, a recent study provided no evidence for the presence of functional ␤ 3 -AR or l.a.s.…”

Section: (ϯ)-(R*r*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]mentioning

confidence: 92%

Role of α-Adrenergic Receptors in the Effect of the β-Adrenergic Receptor Ligands, CGP 12177, Bupranolol, and SR 59230A, on the Contraction of Rat Intrapulmonary Artery

Leblais¹,

Pourageaud²,

Ivorra³

et al. 2004

J Pharmacol Exp Ther

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“…The crystal structure contained the compound cyanopindolol in complex with the protein. This ligand is generally considered to be an antagonist; however, it can behave as a very weak agonist in well‐coupled systems (Brawley et al. , 2000).…”

Section: Impact Of Structure On Understanding Gpcr Functionmentioning

confidence: 99%

The impact of GPCR structures on pharmacology and structure‐based drug design

Congreve

Marshall

2010

British J Pharmacology

124

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After many years of effort, recent technical breakthroughs have enabled the X-ray crystal structures of three G-protein-coupled receptors (GPCRs) (b1 and b2 adrenergic and adenosine A2a) to be solved in addition to rhodopsin. GPCRs, like other membrane proteins, have lagged behind soluble drug targets such as kinases and proteases in the number of structures available and the level of understanding of these targets and their interaction with drugs. The availability of increasing numbers of structures of GPCRs is set to greatly increase our understanding of some of the key issues in GPCR biology. In particular, what constitutes the different receptor conformations that are involved in signalling and the molecular changes which occur upon receptor activation. How future GPCR structures might alter our views on areas such as agonist-directed signalling and allosteric regulation as well as dimerization is discussed. Knowledge of crystal structures in complex with small molecules will enable techniques in drug discovery and design, which have previously only been applied to soluble targets, to now be used for GPCR targets. These methods include structure-based drug design, virtual screening and fragment screening. This review considers how these methods have been used to address problems in drug discovery for kinase and protease targets and therefore how such methods are likely to impact GPCR drug discovery in the future. Pharmacology (2010) 159, 986-996; doi:10.1111/j.1476-5381.2009 published online 13 November 2009 This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j. 1476-5381.2010.00695.x Keywords: G-protein-coupled receptor; X-ray crystallography; structure-based drug design; selectivity; conformation; dimerization; allosteric regulators; fragment screening; virtual screening; rhodopsin Abbreviations: BACE, b-site of APP cleaving enzyme; DPPIV, dipeptidyl peptidase-4; EGFR, epidermal growth factor receptor; FXa, Factor X; GPCR, G-protein-coupled receptor; HDAC, histone deacetylases; HTS, high-throughput screening; NAM, negative allosteric modulator; PAM, positive allosteric modulator; ROCK1, rho-associated; coiledcoil, containing protein kinase 1; SBDD, structure-based drug design; SPR, surface plasmon resonance; TM, transmembrane British Journal of IntroductionHigh-resolution 3-dimensional structures of proteins provide a detailed understanding of the form and function of such proteins at the molecular level. This is useful not only to describe the aspects of protein structure which underlie physiological processes but also in visualizing the intimate connections that bind proteins to their ligands and to small molecule drugs. Although structural studies have been highly successful for soluble proteins, progress in solving the structures of membrane proteins has been relatively poor. G-proteincoupled receptors (GPCRs) represent one of the most important classes of protein due to their critical role in ...

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β₁‐, β₂‐ and atypical β‐adrenoceptor‐mediated relaxation in rat isolated aorta

Cited by 58 publications

References 33 publications

β-Adrenergic cAMP Signals Are Predominantly Regulated by Phosphodiesterase Type 4 in Cultured Adult Rat Aortic Smooth Muscle Cells

β-Adrenergic cAMP Signals Are Predominantly Regulated by Phosphodiesterase Type 4 in Cultured Adult Rat Aortic Smooth Muscle Cells

Role of α-Adrenergic Receptors in the Effect of the β-Adrenergic Receptor Ligands, CGP 12177, Bupranolol, and SR 59230A, on the Contraction of Rat Intrapulmonary Artery

The impact of GPCR structures on pharmacology and structure‐based drug design

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