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      A long-acting β 2-adrenergic agonist increases the expression of muscarine cholinergic subtype-3 receptors by activating the β 2-adrenoceptor cyclic adenosine monophosphate signaling pathway in airway smooth muscle cells

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          Abstract

          The persistent administration of β 2-adrenergic (β 2AR) agonists has been demonstrated to increase the risk of severe asthma, partly due to the induction of tolerance to bronchoprotection via undefined mechanisms. The present study investigated the potential effect of the long-acting β 2-adrenergic agonist, formoterol, on the expression of muscarinic M3 receptor (M 3R) in rat airway smooth muscle cells (ASMCs). Primary rat ASMCs were isolated and characterized following immunostaining with anti-α-smooth muscle actin antibodies. The protein expression levels of M 3R and phospholipase C-β 1 (PLCβ 1) were characterized by western blot analysis and the production of inositol 1,4,5-trisphosphate (IP 3) was determined using an enzyme-linked immunosorbent assay. Formoterol increased the protein expression of M 3R in rat ASMCs in a time- and dose-dependent manner, which was significantly inhibited by the β 2AR antagonist, ICI118,551 and the cyclic adenosine monophosphate (cAMP) inhibitor, SQ22,536. The increased protein expression of M 3R was positively correlated with increased production of PLCβ 1 and IP 3. Furthermore, treatment with the glucocorticoid, budesonide, and the PLC inhibitor, U73,122, significantly suppressed the formoterol-induced upregulated protein expression levels of M 3R and PLCβ 1 and production of IP 3. The present study demonstrated that formoterol mediated the upregulation of M 3R in the rat ASMCs by activating the β 2AR-cAMP signaling pathway, resulting in increased expression levels of PLCβ 1 and IP 3, which are key to inducing bronchoprotection tolerance. Administration of glucocorticoids or a PLC antagonist prevented formoterol-induced bronchoprotection tolerance by suppressing the protein expression of M 3R.

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          Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression.

          cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.
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            Prevalence and etiology of asthma.

            An increased understanding of the causes of asthma is coming from the international comparisons of asthma prevalence, particularly those from the European Community Respiratory Health Survey of asthma prevalence in adults and the International Study of Asthma and Allergies in Childhood. From these and other studies of asthma prevalence, it is possible to draw some tentative conclusions as to the patterns of asthma prevalence worldwide. There are five striking patterns: first, asthma prevalence is increasing worldwide; second, asthma is generally more common in Western countries and less common in developing countries; third, asthma is more prevalent in English-speaking countries; fourth, asthma prevalence is increasing in developing countries as they become more Westernized or communities become urbanized; and fifth, the prevalence of other allergic disorders may also be increasing worldwide. These five key features of the international patterns of asthma prevalence raise major questions about the role of "established" risk factors for the development of asthma. As a result, recent research has expanded to include the study of novel factors that may "program" the initial susceptibility to sensitization or contribute to the development of asthma independent of atopic sensitization. These include various exposures in utero, which are reflected in various perinatal factors measured at birth, and exposures (or lack of exposures) in the early years of life that may make the infant more susceptible to the subsequent development of asthma. These issues are now the focus of an intensive research effort worldwide, and the next few years are likely to see exciting advances in our understanding of the causes of asthma.
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              Beta-adrenergic agonists regulate KCa channels in airway smooth muscle by cAMP-dependent and -independent mechanisms.

              Stimulation of calcium-activated potassium (KCa) channels in airway smooth muscle cells by phosphorylation-dependent and membrane-delimited, G protein actions has been reported (Kume, H. A. Takai, H. Tokuno, and T. Tomita. 1989. Nature [Lond.]. 341:152-154; Kume, H., M. P. Graziano, and M. I. Kotlikoff. 1992. Proc. Natl. Acad. Sci. USA. 89:11051-11055). We show that beta-adrenergic receptor/channel coupling is not affected by inhibition of endogenous ATP, and that activation of KCa channels is stimulated by both alpha S and cAMP-dependent protein kinase (PKA). PKA stimulated channel activity in a dose-dependent fashion with an EC50 of 0.12 U/ml and maximum stimulation of 7.38 +/- 2.04-fold. Application of alpha S to patches near maximally stimulated by PKA significantly increased channel activity to 15.1 +/- 3.65-fold above baseline, providing further evidence for dual regulatory mechanisms and suggesting that the stimulatory actions are independent. Analysis of channel open-time kinetics indicated that isoproterenol and alpha S stimulation of channel activity primarily increased the proportion of longer duration events, whereas PKA stimulation had little effect on the proportion of short and long duration events, but resulted in a significant increase in the duration of the long open-state. cAMP formation during equivalent relaxation of precontracted muscle strips by isoproterenol and forskolin resulted in significantly less cAMP formation by isoproterenol than by forskolin, suggesting that the degree of activation of PKA is not the only determinant of tissue relaxation. We conclude that beta-adrenergic stimulation of KCa channel activity and relaxation of tone in airway smooth muscle occurs, in part, by means independent of cyclic AMP formation.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                June 2015
                05 February 2015
                05 February 2015
                : 11
                : 6
                : 4121-4128
                Affiliations
                [1 ]Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
                [2 ]Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
                [3 ]Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
                Author notes
                Correspondence to: Dr Chun-Tao Liu, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan 610041, P.R. China, E-mail: taosen666@ 123456vip.163.com
                [*]

                Contributed equally

                Article
                mmr-11-06-4121
                10.3892/mmr.2015.3307
                4394984
                25672589
                49215aae-96fd-424c-b7ca-c1f95dd8c650
                Copyright © 2015, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 19 May 2014
                : 09 January 2015
                Categories
                Articles

                airway smooth muscle cells,β2-adrenoceptor agonists,bronchoprotection,formoterol,muscarine cholinergic subtype 3 receptor,phospholipase c-β1

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