Details

Autor(en) / Beteiligte

• Elagoz, Aram
• Henderson, Duncan
• Babu, Poda Suresh
• Salter, Sylvia
• Grahames, Caroline
• Bowers, Lorna
• Roy, Marie‐Odile
• Laplante, Patricia
• Grazzini, Eric
• Ahmad, Sultan
• Lembo, Paola M C

Titel

A truncated form of CKβ8‐1 is a potent agonist for human formyl peptide‐receptor‐like 1 receptor

Ist Teil von

• British journal of pharmacology, 2004-01, Vol.141 (1), p.37-46

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2004

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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 β‐chemokine receptor for an N‐terminally truncated form of the CKβ8 (CCL23/MPIF‐1) splice variant CKβ8‐1 (22–137 aa). RT‐PCR analysis of mRNA derived from human tissues and cells revealed a predominant expression of FPRL‐1 in inflammatory cells, particularly in neutrophils. 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 Gα16, demonstrated FPRL‐1 is a functional high‐affinity receptor for CKβ8‐1 (46–137 aa, sCKβ8‐1), with pEC50 values of 9.13 and 8.85, respectively. The FPRL‐1 activation in CHO‐K1 cells is mediated by Gαi/Gαo proteins, as assessed by pertussis toxin sensitivity and inhibition of forskolin‐induced cyclic AMP accumulation. 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 Kd value of 9.34. Many known FPRL‐1 agonists were tested and sCKβ8‐1 was the most effective nonsynthetic ligand in displacing the radiolabelled agonist, with a pIC50 of 7.97. The functional significance of sCKβ8‐1 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. British Journal of Pharmacology (2004) 141, 37–46. doi:10.1038/sj.bjp.0705592