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Occupancy of adenosine A2a receptors promotes fMLP‐induced cyclic AMP accumulation in human neutrophils: impact on phospholipase D activity and recruitment of small GTPases to membranes
Author(s) -
Thibault Nathalie,
Burelout Chantal,
Harbour Danielle,
Borgeat Pierre,
Naccache Paul H.,
Bourgoin Sylvain G.
Publication year - 2002
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.71.2.367
Subject(s) - adenylyl cyclase , agonist , adenosine , activator (genetics) , forskolin , phosphodiesterase , biology , medicine , phosphodiesterase inhibitor , pde10a , endocrinology , receptor , rhoa , signal transduction , stimulation , microbiology and biotechnology , biochemistry , enzyme
The aim of this study was to assess in human neutrophils theimplication of an adenosine 3′,5′‐cyclic monophosphate (cAMP)‐dependentpathway in the inhibitory effects of A2a receptor engagement. We foundthat Ro20‐1724, a cAMP phosphodiesterase inhibitor, in the presence ofadenosine deaminase (ADA) or A2a receptor antagonists renderedtransient the fMLP‐induced sustained increases in cAMP levels. The roleof A2a receptor stimulation was demonstrated by the ability of the A2areceptor agonist, CGS21680, to prevent ADA‐mediated reduction of thepersistent cAMP elevation induced by fMLP. Persistent cAMP elevationcorrelated with inhibition of fMLP‐induced PLD activation andrecruitment of Arf, RhoA, and PKC to membranes. The suppressive effectof CGS21680 or isoproterenol, a β‐adrenergic receptor agonist, wasincreased by Ro20‐1724 or by the adenylyl cyclase activator, forskolin, and reversed, at least in part, by the inhibitor of adenylyl cyclase,2′,5′‐dideoxyadenosine. The activator of protein kinase A (PKA),Sp‐cAMP inhibited fMLP‐induced PLD activation and translocation of Arfand RhoA to membranes. In contrast, the suppression by A2a receptorstimulation of fMLP‐induced PLD activation and cofactor recruitment wasantagonized by PKA inhibitors, Rp‐cAMP and H89. In conclusion, A2areceptor occupancy by extracellular adenosine inhibits fMLP‐inducedneutrophil activation via cAMP and PKA‐regulated events.