Pituitary adenylate cyclase-activating polypeptide 27 is a functional ligand for formyl peptide receptor-like 1.
Although the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in the regulation of several immune responses, its target receptors and signaling mechanisms have yet to be fully elucidated in immune cells. In this study, we found that PACAP27, but not PACAP38, specifically stimulated intracellular calcium mobilization and ERK phosphorylation in human neutrophils. Moreover, formyl peptide receptor-like 1 (FPRL1) was identified as a PACAP27 receptor, and PACAP27 was found to selectively stimulate intracellular calcium increase in FPRL1-transfected rat basophil leukocytes-2H3 cell lines. In addition, PACAP27-induced calcium increase and ERK phosphorylation were specifically inhibited by an FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), thus supporting the notion that PACAP27 acts on FPRL1. In terms of the functional role of PACAP27, we found that the peptide stimulated CD11b surface up-regulation and neutrophil chemotactic migration, and that these responses were completely inhibited by WRW4. The interaction between PACAP27 and FPRL1 was analyzed further using truncated PACAPs and chimeric PACAPs using vasoactive intestinal peptide, and the C-terminal region of PACAP27 was found to perform a vital function in the activation of FPRL1. Taken together, our study suggests that PACAP27 activates phagocytes via FPRL1 activation, and that this results in proinflammatory behavior, involving chemotaxis and the up-regulation of CD11b.
Kim
Youndong
Y
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Korea.
Lee
Byoung Dae
BD
Kim
Oekyung
O
Bae
Yoe-Sik
YS
Lee
Taehoon
T
Suh
Pann-Ghill
PG
Ryu
Sung Ho
SH
D000595:Amino Acid Sequence; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism* / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D039481:CD11b Antigen; C105101:FPR2 protein, human; D008024:Ligands; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D048049:Extracellular Signal-Regulated MAP Kinases