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A pepducin designed to modulate P2Y2R function interacts with FPR2 in human neutrophils and transfers ATP to an NADPH-oxidase-activating ligand through a receptor cross-talk mechanism.

Artikel i vetenskaplig tidskrift
Författare Michael Gabl
André Holdfeldt
Malene Winther
Tudor I Oprea
Johan Bylund
Claes Dahlgren
Huamei Forsman
Publicerad i Biochimica et biophysica acta
Volym 1863
Nummer/häfte 6 Pt A
Sidor 1228-37
ISSN 0006-3002
Publiceringsår 2016
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Institutionen för odontologi, sektion 3
Sidor 1228-37
Språk en
Länkar dx.doi.org/10.1016/j.bbamcr.2016.03...
Ämnesord Adenosine Triphosphate, metabolism, Amino Acid Sequence, Binding, Competitive, drug effects, Calcium, metabolism, Cells, Cultured, HL-60 Cells, Humans, Ligands, Molecular Sequence Data, NADPH Oxidase, metabolism, Neutrophils, cytology, drug effects, metabolism, Oxygen, metabolism, Peptides, metabolism, pharmacology, Protein Binding, drug effects, Receptor Cross-Talk, drug effects, Receptors, Formyl Peptide, metabolism, Receptors, Lipoxin, metabolism, Receptors, Purinergic P2Y2, chemistry, metabolism, Time Factors
Ämneskategorier Klinisk medicin, Medicinska grundvetenskaper

Sammanfattning

Several G-protein-coupled receptors (GPCRs) can be activated or inhibited in a specific manner by membrane-permeable pepducins, which are short palmitoylated peptides with amino acid sequences identical to an intracellular domain of the receptor to be targeted. Unlike the endogenous P2Y2R agonist ATP, the P2Y2PalIC2 pepducin, which has an amino acid sequence corresponding to the second intracellular loop of the human ATP receptor (P2Y2R), activated the superoxide anion-generating NADPH-oxidase in neutrophils. In addition to having a direct effect on neutrophils, the P2Y2R pepducin converted naïve neutrophils to a primed state, which secondarily responded to ATP by producing superoxide. A pepducin with a peptide identical to the third intracellular loop of P2Y2R (P2Y2PalIC3) exhibited the same basic functions as P2Y2PalIC2, whereas one with a peptide that was identical to the first intracellular loop (P2Y2PalIC1) lacked these functions. The responses induced in neutrophils by the P2Y2R pepducins were not inhibited by the P2Y2R antagonist AR-C118925, and the receptor desensitization profile suggested the involvement of FPR2 rather than P2Y2R. Accordingly, antagonists/inhibitors of FPR2 attenuated the activities of the P2Y2R pepducins, which also selectively activated FPR2-overexpressing cells. In summary, we show that pepducins supposed to target P2Y2R activate human neutrophils through FPR2. We also show that the P2Y2PalIC2 pepducin can convert ATP from a non-activating agent to a potent neutrophil NADPH-oxidase activator. The molecular basis of this phenomenon involves cross-talk between the receptor/ligand pairs of P2Y2R/ATP and FPR2/P2Y2-pepducin.

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