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PMID: 14662730 Published · ppublish English Journal Article

A truncated form of CKbeta8-1 is a potent agonist for human formyl peptide-receptor-like 1 receptor.

British journal of pharmacology ·Vol. 141 ·No. 1 ·2004-01-00 ·Pages 37-46

Elagoz A, Henderson D, Babu PS, Salter S, Grahames C, Bowers L, Roy MO, Laplante P, Grazzini E, Ahmad S, Lembo PM

Abstract

1. Human formyl peptide-receptor-like-1 (FPRL-1) is a promiscuous G protein-coupled receptor (GPCR), and belongs to a chemoattractant receptor family protein. This receptor has been reported to interact with various host-derived peptides and lipids involved in inflammatory responses. We described here, a novel role for FPRL-1 as a high-affinity beta-chemokine receptor for an N-terminally truncated form of the CKbeta8 (CCL23/MPIF-1) splice variant CKbeta8-1 (22-137 aa). 2. RT-PCR analysis of mRNA derived from human tissues and cells revealed a predominant expression of FPRL-1 in inflammatory cells, particularly in neutrophils. 3. Intracellular calcium mobilisation assay, used as screening tool, in recombinant Chinese hamster ovary (CHO-K1) and human embryonic kidney (HEK293s) cells coexpressing FPRL-1 and Galpha(16), demonstrated FPRL-1 is a functional high-affinity receptor for CKbeta8-1 (46-137 aa, sCKbeta8-1), with pEC(50) values of 9.13 and 8.85, respectively. 4. The FPRL-1 activation in CHO-K1 cells is mediated by Galpha(i)/Galpha(o) proteins, as assessed by pertussis toxin sensitivity and inhibition of forskolin-induced cyclic AMP accumulation. 5. Binding experiments were performed with a radio-iodinated synthetic peptide, [(125-)I]-WKYMVm, a known potent FPRL-1 agonist. CHO-K1 cell membranes expressing FPRL-1 bound [(125-)I]-WKYMVm with a K(d) value of 9.34. Many known FPRL-1 agonists were tested and sCKbeta8-1 was the most effective nonsynthetic ligand in displacing the radiolabelled agonist, with a pIC(50) of 7.97. 6. The functional significance of sCKbeta8-1 interaction with FPRL-1 was further demonstrated by the activation of polymorphonuclear leukocytes (PMNs) calcium mobilisation and chemotaxis. These interactions were shown to be via FPRL-1 by specific blockade of PMNs activation in the presence of an FPRL-1 antibody.

MeSH Terms
Amino Acid Sequence Animals CHO Cells Calcium/metabolism Cell Movement/drug effects Chemokines, CC/chemistry,metabolism,pharmacology Chemotaxis/drug effects Cricetinae Drug Evaluation, Preclinical/methods Female GTP-Binding Protein alpha Subunits, Gi-Go/chemistry,metabolism Gene Expression Humans Iodine Radioisotopes/metabolism Kidney/cytology,drug effects Neutrophils/drug effects,metabolism Polymerase Chain Reaction/methods RNA, Messenger/genetics Receptors, Formyl Peptide/drug effects,genetics,metabolism Receptors, G-Protein-Coupled Receptors, Lipoxin/drug effects,genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction
Chemicals
CCL23 protein, human Chemokines, CC FPR2 protein, human Iodine Radioisotopes RNA, Messenger Receptors, Formyl Peptide Receptors, G-Protein-Coupled Receptors, Lipoxin GTP-Binding Protein alpha Subunits, Gi-Go Calcium
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Elagoz Aram
AstraZeneca R&D Montréal, 7171 Frederick-Banting, Ville Saint-Laurent, Québec, Canada, H4S 1Z9. [email protected]
Henderson Duncan
Babu Poda Suresh
Salter Sylvia
Grahames Caroline
Bowers Lorna
Roy Marie-Odile
Laplante Patricia
Grazzini Eric
Ahmad Sultan
Lembo Paola M C
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0705592
Email
[email protected]
Published
2004-01-00
Epub
2003-00-08
Pages
37-46
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1574175
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0705592 PMC Full Text View journal details
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