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The leukocyte chemotactic receptor FPR2, but not the closely related FPR1, is sensitive to cell-penetrating pepducins with amino acid sequences descending from the third intracellular receptor loop.

Artikel i vetenskaplig tidskrift
Författare Huamei Forsman
Johan Bylund
Tudor I Oprea
Anna Karlsson
Francois Boulay
Marie-Josephe Rabiet
Claes Dahlgren
Publicerad i Biochimica et biophysica acta
Volym 1833
Nummer/häfte 8
Sidor 1914-1923
ISSN 0006-3002
Publiceringsår 2013
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Sidor 1914-1923
Språk en
Länkar dx.doi.org/10.1016/j.bbamcr.2013.03...
https://gup.ub.gu.se/file/110000
Ämnesord Neutrophils, G-protein coupled chemoattractant receptor (GPCR), Formyl peptide receptor (FPR), Pepducins
Ämneskategorier Klinisk medicin

Sammanfattning

Lipidated peptides (pepducins) can activate certain G-protein coupled receptors (GPCRs) through a unique allosteric modulation mechanism involving cytosolic receptor domains. Pepducins with the amino acid sequence of the third intracellular loop of the neutrophil formyl peptide receptors (FPRs) as a common denominator were N-terminally conjugated with palmitic acid. F2Pal16, containing the 16 amino acids present in the third intracellular loop of FPR2, induced superoxide production in human neutrophils and the activity was sensitive to FPR2 antagonists. Cells over-expressing FPR2 were similarly responsive and responded with a transient increase in cytosolic calcium. No such effects were observed with the corresponding FPR1 pepducin. The peptide alone, lacking palmitic acid, did not activate neutrophils. A ten amino acid long pepducin F2Pal10, that was a more potent neutrophil activator than F2Pal16, was used for amino acid substitution studies. The sequences of FPR1 and FPR2 in the third intracellular loop differ by only two amino acids, and a pepducin with the FPR2-specific K231 replaced by the FPR1-specific Q231 lost all activity. The active F2Pal10 pepducin also triggered a response in cells expressing a mutated FPR2 with the third intracellular loop identical to that of FPR1. The data presented suggest that the same signaling pathways are activated when the signaling cascade is initiated by a classical receptor agonist (outside-in signaling) and when signaling starts on the cytosolic side of the membrane by a pepducin (inside-in signaling). A fundamental difference is also disclosed between the two neutrophil FPRs regarding their sensitivities to third intracellular loop pepducins.

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