Development and Characterization of Pepducins as Gs-biased Allosteric Agonists

The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promote...

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Published inThe Journal of biological chemistry Vol. 289; no. 52; pp. 35668 - 35684
Main Authors Carr, Richard, Du, Yang, Quoyer, Julie, Panettieri, Reynold A., Janz, Jay M., Bouvier, Michel, Kobilka, Brian K., Benovic, Jeffrey L.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 26.12.2014
American Society for Biochemistry and Molecular Biology
Subjects
Adrenergic beta-Agonists - pharmacology
Adrenergic Receptor
Allosteric Regulation
Amino Acid Sequence
Asthma
Biased Agonist
Cyclic AMP - biosynthesis
Drug Discovery
Functional Selectivity
G Protein-coupled Receptor (GPCR)
GTP-Binding Protein alpha Subunits, Gs - metabolism
HEK293 Cells
Humans
Molecular Sequence Data
Pepducin
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptide Library
Peptides
Phosphorylation
Protein Binding
Protein Processing, Post-Translational
Protein Structure, Tertiary
Protein Transport
Receptors, Adrenergic, beta-2 - chemistry
Receptors, Adrenergic, beta-2 - metabolism
Second Messenger Systems
Signal Transduction
β2-Adrenergic Receptor
Functional Selectivity
Peptides
Signal Transduction
Adrenergic Receptor
Pepducin
β2-Adrenergic Receptor
Biased Agonist
Drug Discovery
G Protein-coupled Receptor (GPCR)
Asthma
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Abstract The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.A Gs-biased agonist for the β2-adrenergic receptor (β2AR) has yet to be reported. A screen of β2AR pepducins identified receptor-dependent and receptor-independent pepducins that selectively activate Gs. Receptor-dependent pepducins promote a Gs-biased conformation of the β2AR, whereas receptor-independent pepducins directly activate Gs. Gs-biased pepducins provide a valuable tool for the continued study of β2AR function and may prove useful as next-generation asthma therapeutics.
AbstractList Background: A G s -biased agonist for the β 2 -adrenergic receptor (β 2 AR) has yet to be reported. Results: A screen of β 2 AR pepducins identified receptor-dependent and receptor-independent pepducins that selectively activate G s . Conclusion: Receptor-dependent pepducins promote a G s -biased conformation of the β 2 AR, whereas receptor-independent pepducins directly activate G s . Significance: G s -biased pepducins provide a valuable tool for the continued study of β 2 AR function and may prove useful as next-generation asthma therapeutics. The β 2 -adrenergic receptor (β 2 AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β 2 AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β 2 AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β 2 AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-G s coupling and promote β 2 AR internalization and degradation. A biased agonist that can selectively stimulate G s signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β 2 AR, known as pepducins. This screen revealed two classes of G s -biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent G s -biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent G s -biased pepducins appear to stabilize a G s -biased conformation of the β 2 AR that couples to G s but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that G s -biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first G s -biased activator of the β 2 AR and provides valuable tools for the study of β 2 AR function.
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.A Gs-biased agonist for the β2-adrenergic receptor (β2AR) has yet to be reported. A screen of β2AR pepducins identified receptor-dependent and receptor-independent pepducins that selectively activate Gs. Receptor-dependent pepducins promote a Gs-biased conformation of the β2AR, whereas receptor-independent pepducins directly activate Gs. Gs-biased pepducins provide a valuable tool for the continued study of β2AR function and may prove useful as next-generation asthma therapeutics.
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.
Author Bouvier, Michel
Kobilka, Brian K.
Panettieri, Reynold A.
Carr, Richard
Janz, Jay M.
Quoyer, Julie
Du, Yang
Benovic, Jeffrey L.
Author_xml – sequence: 1
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  surname: Carr
  fullname: Carr, Richard
  organization: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
– sequence: 2
  givenname: Yang
  surname: Du
  fullname: Du, Yang
  organization: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305
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  givenname: Julie
  surname: Quoyer
  fullname: Quoyer, Julie
  organization: Department of Biochemistry and Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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  givenname: Reynold A.
  surname: Panettieri
  fullname: Panettieri, Reynold A.
  organization: Department of Medicine, Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104
– sequence: 5
  givenname: Jay M.
  surname: Janz
  fullname: Janz, Jay M.
  organization: Department of Anchor Therapeutics, Cambridge, Massachusetts 02139
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  givenname: Brian K.
  surname: Kobilka
  fullname: Kobilka, Brian K.
  organization: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305
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  givenname: Jeffrey L.
  surname: Benovic
  fullname: Benovic, Jeffrey L.
  email: jeffrey.benovic@jefferson.edu
  organization: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25395624$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright 2014 © 2014 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
2014 by The American Society for Biochemistry and Molecular Biology, Inc.
2014 by The American Society for Biochemistry and Molecular Biology, Inc. 2014
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– notice: 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
– notice: 2014 by The American Society for Biochemistry and Molecular Biology, Inc. 2014
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IsScholarly true
Issue 52
Keywords Functional Selectivity
Peptides
Signal Transduction
Adrenergic Receptor
Pepducin
β2-Adrenergic Receptor
Biased Agonist
Drug Discovery
G Protein-coupled Receptor (GPCR)
Asthma
Language English
License This is an open access article under the CC BY license.
http://creativecommons.org/licenses/by/4.0
https://www.elsevier.com/tdm/userlicense/1.0
2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Present address: Pfizer Rare Disease Research Unit, Cambridge, MA 02140.
OpenAccessLink https://dx.doi.org/10.1074/jbc.M114.618819
PMID 25395624
PQID 1640851319
PQPubID 23479
PageCount 17
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crossref_citationtrail_10_1074_jbc_M114_618819
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PublicationDate 2014-12-26
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PublicationDate_xml – month: 12
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  day: 26
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PublicationTitle The Journal of biological chemistry
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American Society for Biochemistry and Molecular Biology
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Snippet The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary...
Background: A G s -biased agonist for the β 2 -adrenergic receptor (β 2 AR) has yet to be reported. Results: A screen of β 2 AR pepducins identified...
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SubjectTerms Adrenergic beta-Agonists - pharmacology
Adrenergic Receptor
Allosteric Regulation
Amino Acid Sequence
Asthma
Biased Agonist
Cyclic AMP - biosynthesis
Drug Discovery
Functional Selectivity
G Protein-coupled Receptor (GPCR)
GTP-Binding Protein alpha Subunits, Gs - metabolism
HEK293 Cells
Humans
Molecular Sequence Data
Pepducin
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptide Library
Peptides
Phosphorylation
Protein Binding
Protein Processing, Post-Translational
Protein Structure, Tertiary
Protein Transport
Receptors, Adrenergic, beta-2 - chemistry
Receptors, Adrenergic, beta-2 - metabolism
Second Messenger Systems
Signal Transduction
β2-Adrenergic Receptor
Title Development and Characterization of Pepducins as Gs-biased Allosteric Agonists
URI https://dx.doi.org/10.1074/jbc.M114.618819
https://www.ncbi.nlm.nih.gov/pubmed/25395624
https://www.proquest.com/docview/1640851319
https://pubmed.ncbi.nlm.nih.gov/PMC4276837
Volume 289
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