title: V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins.
abstract: Genetic 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-G(α16) 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(101)) displayed significantly higher pK(i) values for CsA and CsH (cyclosporin H), indicative of an improved receptor affinity. The polymorphism of FPR1 p.Leu(101) 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(101) allele of FPR1.
authors: The National Center for Drug Screening, the Chinese Academy of Sciences Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
authors: Caihong
authors: C
authors: Zhou
authors: Yan
authors: Y
authors: Zhou
authors: Jia
authors: J
authors: Wang
authors: Yang
authors: Y
authors: Feng
authors: Haonan
authors: H
authors: Wang
authors: Jinglun
authors: J
authors: Xue
authors: Yani
authors: Y
authors: Chen
authors: Richard D
authors: RD
authors: Ye
authors: Ming-Wei
authors: MW
authors: Wang
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D044466:Asian People; D016466:CHO Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D044042:Receptors, Formyl Peptide / Q000235:genetics* / Q000378:metabolism*
chemical_list: D003524:Cyclosporins; C469986:FPR1 protein, human; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016572:Cyclosporine; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
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