Development and characterization of pepducins as Gs-biased allosteric agonists

Richard Carr, Yang Du, Julie Quoyer, Reynold A. Panettieri, Jay M. Janz, Michel Bouvier, Brian K. Kobilka, Jeffrey L. Benovic

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65 Citations (Scopus)


The β2-adrenergic receptor (β2AR) is a prototypical G pro-tein- 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 recep-tor- independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependentG s-biased pepducins appear to stabilize aGs-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.

Original languageEnglish
Pages (from-to)35668-35684
Number of pages17
JournalJournal of Biological Chemistry
Issue number52
Publication statusPublished - 26 Dec 2014
Externally publishedYes


  • andrenergic receptor
  • asthma
  • drug discovery
  • G protein-coupled receptor (GPCR)
  • peptides
  • signal transduction
  • B2-Adrenergic receptor
  • pepducin
  • biased agonist
  • functional selectivity

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