A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide

Karin Önnheim; Karin Christenson; Michael Gabl; Joachim C Burbiel; Christa E Müller; Tudor I Oprea; Johan Bylund; Claes Dahlgren; Huamei Forsman

doi:10.1016/j.yexcr.2014.01.023

A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide

Exp Cell Res. 2014 Apr 15;323(1):209-217. doi: 10.1016/j.yexcr.2014.01.023. Epub 2014 Feb 1.

Authors

Karin Önnheim¹, Karin Christenson¹, Michael Gabl¹, Joachim C Burbiel², Christa E Müller², Tudor I Oprea³, Johan Bylund¹, Claes Dahlgren¹, Huamei Forsman⁴

Affiliations

¹ Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Göteborg 413 46, Sweden.
² PharmaCenter Bonn, Pharmaceutical Chemistry I at the Pharmaceutical Institute, University of Bonn, Bonn, Germany.
³ Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Göteborg 413 46, Sweden; Division of Biocomputing, Department of Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
⁴ Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Göteborg 413 46, Sweden. Electronic address: Huamei.forsman@rheuma.gu.se.

PMID: 24491917
DOI: 10.1016/j.yexcr.2014.01.023

Abstract

Neutrophils express several G-protein coupled receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized formyl peptide receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca(2+) transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.

Keywords: ATP; Cross-talk; Formyl peptides; G-protein coupled receptors; Neutrophils.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton
Adenosine Triphosphate / metabolism*
Antineoplastic Agents / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Calcium / metabolism
Cyclosporine / pharmacology
Enzyme Inhibitors / pharmacology
Humans
Marine Toxins
NADPH Oxidases / metabolism
Neutrophil Activation / immunology
Neutrophils / metabolism*
Oxazoles / pharmacology
Phosphoprotein Phosphatases / antagonists & inhibitors
Purinergic P2Y Receptor Antagonists / pharmacology
Receptors, Formyl Peptide / metabolism*
Receptors, Purinergic P2Y2 / metabolism*
Signal Transduction / drug effects
Superoxides / metabolism
Suramin / pharmacology
Thiazolidines / pharmacology

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Enzyme Inhibitors
FPR1 protein, human
Marine Toxins
Oxazoles
Purinergic P2Y Receptor Antagonists
Receptors, Formyl Peptide
Receptors, Purinergic P2Y2
Thiazolidines
Superoxides
Suramin
calyculin A
Cyclosporine
Adenosine Triphosphate
NADPH Oxidases
Phosphoprotein Phosphatases
cyclosporin H
latrunculin A
Calcium