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V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins
Zhou C.2; Zhou Y.2; Wang J.2; Feng Y.2; Wang H.2; Xue J.4; Chen Y.1; Ye R.D.3; Wang M.-W.2
2013-04-15
Source PublicationBiochemical Journal
ISSN02646021 14708728
Volume451Issue:2Pages:245-255
AbstractGenetic variation plays a major role in drug response variability. CsA (cyclosporin A), a widely used immunosuppressive agent, is a specific antagonist for FPR1 (formyl peptide receptor 1), which is an important G-protein-coupled chemoattractant receptor in the innate immune system. In order to study the variable responses of cyclosporins to different FPR1 mutants, we investigated the distribution of human FPR1 haplotypes among 209 healthy Han Chinese subjects. The haplotype pattern in Han Chinese were characterized on the basis of five SNPs (single nucleotide polymorphisms), including rs5030878 (p.T11I), rs2070745 (p.V101L), rs5030880 (p.R190W), rs1042229 (p.N192K) and rs867228 (p.A346E). Receptor binding affinity of cyclosporins to FPR1 haplotypes was assessed using N-formyl-Nle-Leu-Phe- Nle-Tyr-Lys-FITC in CHO- Gα cells stably transfected with cDNAs encoding the top 12 FPR1 haplotypes in the Han Chinese. Variants of FPR1 carrying a single amino acid substitution of leucine for valine at position 101 (p.Leu) displayed significantly higher pKi values for CsA and CsH (cyclosporin H), indicative of an improved receptor affinity. The polymorphism of FPR1 p.Leu also enhanced the inhibitory effects of cyclosporins on fMLF (N-formyl-methionyl-leucyl-phenylalanine)-induced activities, including calcium mobilization, cell chemotaxis and MAPK (mitogen-activated protein kinase) phosphorylation. These results point to a possible complication for clinical use of CsA in patients carrying the p.Leu allele of FPR1. © 2013 Biochemical Society.
KeywordCyclosporin Formyl peptide receptor 1 (FPR1) Haplotype Pharmacogenomics Receptor affinity Single nucleotide polymorphism
DOI10.1042/BJ20121839
URLView the original
Language英語
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Cited Times [WOS]:7   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Shanghai ADICON Clinical Laboratories
2.Chinese Academy of Sciences
3.Shanghai Jiao Tong University
4.Fudan University
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GB/T 7714
Zhou C.,Zhou Y.,Wang J.,et al. V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins[J]. Biochemical Journal,2013,451(2):245-255.
APA Zhou C..,Zhou Y..,Wang J..,Feng Y..,Wang H..,...&Wang M.-W..(2013).V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins.Biochemical Journal,451(2),245-255.
MLA Zhou C.,et al."V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins".Biochemical Journal 451.2(2013):245-255.
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