Dissociations in the effects of beta2-adrenergic receptor agonists on cAMP formation and superoxide production in human neutrophils: Support for the concept of functional selectivity

URN to cite this document:

urn:nbn:de:bvb:355-epub-279724 Copy

DOI to cite this document:

10.5283/epub.27972 Copy

Brunskole Hummel, Irena ; Kälble, Solveig ; Burhenne, Heike ; Reinartz, Michael T. ; Schwede, Frank ; Buschauer, Armin ; Seifert, Roland

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Date of publication of this fulltext: 26 Apr 2013 05:19

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Details

Item type:	Article
Journal or Publication Title:	PLoS One
Volume:	8
Number of Issue or Book Chapter:	5
Page Range:	e64556
Date:	31 May 2013
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
Identification Number:	Value Type doi:10.1371/journal.pone.0064556 DOI
Keywords:	β2-adrenergic receptor, neutrophil, adenosine-3',5'-cyclic monophosphate, superoxide anion, functional selectivity
Dewey Decimal Classification:	600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Partially
Item ID:	27972

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Abstract

In neutrophils, activation of the beta2-adrenergic receptor (beta2AR), a Gs-coupled receptor, inhibits inflammatory responses, which could be therapeutically exploited. The aim of this study was to evaluate the effects of various beta2AR ligands on adenosine-3',5'-cyclic monophosphate (cAMP) accumulation and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O2*-) ...

Abstract

In neutrophils, activation of the beta2-adrenergic receptor (beta2AR), a Gs-coupled receptor,
inhibits inflammatory responses, which could be therapeutically exploited. The aim of this study was to
evaluate the effects of various beta2AR ligands on adenosine-3',5'-cyclic monophosphate (cAMP)
accumulation and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion
(O2*-) production in human neutrophils and to probe the concept of ligand-specific receptor
conformations (also referred to as functional selectivity or biased signaling) in a native cell system.
cAMP concentration was determined by HPLC/tandem mass spectrometry, and O2*- formation was
assessed by superoxide dismutase-inhibitable reduction of ferricytochrome c. beta2AR agonists were
generally more potent in inhibiting fMLP-induced O2*- production than in stimulating cAMP
accumulation. (-)-Ephedrine and dichloroisoproterenol were devoid of any agonistic activity in the
cAMP assay, but partially inhibited fMLP-induced O2*- production. Moreover, (-)-adrenaline was equiefficacious
in both assays whereas the efficacy of salbutamol was more than two-fold higher in the O2*-
assay. In contrast to the agonists, the effects of beta2AR antagonists were comparable between the two
parameters on neutrophils. Differences between the data from neutrophils and recombinant test
systems were observed for the beta2AR agonists as well as for the beta2AR antagonists. Lastly, we
obtained no evidence for an involvement of protein kinase A in the inhibition of fMLP-induced O2*-
production after beta2AR-stimulation, although, in principle, cAMP-increasing substances can inhibit
O2*- production. Taken together, our data corroborate the concept of ligand-specific receptor
conformations with unique signaling capabilities and suggest that the beta2AR inhibits O2*-
production in a cAMP-independent manner.

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