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.
The aim of this study was to assess in human neutrophils the implication of an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway in the inhibitory effects of A2a receptor engagement. We found that Ro20-1724, a cAMP phosphodiesterase inhibitor, in the presence of adenosine deaminase (ADA) or A2a receptor antagonists rendered transient the fMLP-induced sustained increases in cAMP levels. The role of A2a receptor stimulation was demonstrated by the ability of the A2a receptor agonist, CGS21680, to prevent ADA-mediated reduction of the persistent cAMP elevation induced by fMLP. Persistent cAMP elevation correlated with inhibition of fMLP-induced PLD activation and recruitment of Arf, RhoA, and PKC to membranes. The suppressive effect of CGS21680 or isoproterenol, a beta-adrenergic receptor agonist, was increased 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 Arf and RhoA to membranes. In contrast, the suppression by A2a receptor stimulation of fMLP-induced PLD activation and cofactor recruitment was antagonized by PKA inhibitors, Rp-cAMP and H89. In conclusion, A2a receptor occupancy by extracellular adenosine inhibits fMLP-induced neutrophil activation via cAMP and PKA-regulated events.
Thibault
Nathalie
N
CIHR Group on the Molecular Mechanisms of Inflammation, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUL, CHUQ et Université Laval, Département d'Anatomie-Physiologie, Sainte-Foy, Québec, Canada.
Burelout
Chantal
C
Harbour
Danielle
D
Borgeat
Pierre
P
Naccache
Paul H
PH
Bourgoin
Sylvain G
SG
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010739:Phospholipase D / Q000502:physiology*; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D010739:Phospholipase D; D000243:Adenosine Deaminase; D020559:Monomeric GTP-Binding Proteins