G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action
Identifieur interne : 000B01 ( Pmc/Curation ); précédent : 000B00; suivant : 000B02G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action
Auteurs : Stacy Gelhaus Wendell ; Hao Fan ; Cheng ZhangSource :
- Pharmacological Reviews [ 0031-6997 ] ; 2020.
Abstract
Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein–coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting
Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein
Url:
DOI: 10.1124/pr.118.016899
PubMed: 31767622
PubMed Central: 6878000
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<author><name sortKey="Fan, Hao" sort="Fan, Hao" uniqKey="Fan H" first="Hao" last="Fan">Hao Fan</name>
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<author><name sortKey="Zhang, Cheng" sort="Zhang, Cheng" uniqKey="Zhang C" first="Cheng" last="Zhang">Cheng Zhang</name>
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<series><title level="j">Pharmacological Reviews</title>
<idno type="ISSN">0031-6997</idno>
<idno type="eISSN">1521-0081</idno>
<imprint><date when="2020">2020</date>
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<front><div type="abstract" xml:lang="en"><p>Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein–coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting <italic>β</italic>
<sub>2</sub>
-agonists are widely used bronchodilators that signal through the activation of the <italic>β</italic>
<sub>2</sub>
-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D<sub>2</sub>
receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A<sub>2B</sub>
receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment.</p>
<sec><title>SIGNIFICANCE STATEMENT</title>
<p>Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein<bold>–</bold>
coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.</p>
</sec>
</div>
</front>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmacol Rev</journal-id>
<journal-id journal-id-type="iso-abbrev">Pharmacol. Rev</journal-id>
<journal-id journal-id-type="hwp">pharmrev</journal-id>
<journal-id journal-id-type="pmc">Pharmacol Rev</journal-id>
<journal-id journal-id-type="publisher-id">PharmRev</journal-id>
<journal-title-group><journal-title>Pharmacological Reviews</journal-title>
</journal-title-group>
<issn pub-type="ppub">0031-6997</issn>
<issn pub-type="epub">1521-0081</issn>
<publisher><publisher-name>The American Society for Pharmacology and Experimental Therapeutics</publisher-name>
<publisher-loc>Bethesda, MD</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31767622</article-id>
<article-id pub-id-type="pmc">6878000</article-id>
<article-id pub-id-type="publisher-id">PHARMREV_016899</article-id>
<article-id pub-id-type="doi">10.1124/pr.118.016899</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action<xref ref-type="fn" rid="FN1"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic>
</sup>
</xref>
</article-title>
<alt-title alt-title-type="short">Pharmacology of GPCRs in Asthma Therapy and Drug Action</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Wendell</surname>
<given-names>Stacy Gelhaus</given-names>
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</contrib>
<contrib contrib-type="author"><name><surname>Fan</surname>
<given-names>Hao</given-names>
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<xref ref-type="corresp" rid="cor1"></xref>
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<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Cheng</given-names>
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<xref ref-type="corresp" rid="cor2"></xref>
</contrib>
<aff>Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Insel</surname>
<given-names>Paul A.</given-names>
</name>
<role>ASSOCIATE EDITOR</role>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1"><bold>Address correspondence to:</bold>
Dr. Hao Fan, Bioinformatics Institute, A*STAR, 30 Biopolis Street, Matrix #07-01, Singapore 138671. E-mail: <email>fanh@bii.a-star.edu.sg</email>
or </corresp>
<corresp id="cor2">Dr. Cheng Zhang, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15261. E-mail: <email>chengzh@pitt.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="pmc-release"><month>1</month>
<year>2020</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the . </pmc-comment>
<volume>72</volume>
<issue>1</issue>
<fpage>1</fpage>
<lpage>49</lpage>
<permissions><copyright-statement>Copyright © 2019 by The Author(s)</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This is an open access article distributed under the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC Attribution 4.0 International license</ext-link>
.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:href="pr.118.016899.pdf"></self-uri>
<abstract><p>Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein–coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting <italic>β</italic>
<sub>2</sub>
-agonists are widely used bronchodilators that signal through the activation of the <italic>β</italic>
<sub>2</sub>
-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D<sub>2</sub>
receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A<sub>2B</sub>
receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment.</p>
<sec><title>SIGNIFICANCE STATEMENT</title>
<p>Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein<bold>–</bold>
coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.</p>
</sec>
</abstract>
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