V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins

doi:10.1042/BJ20121839

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins
	Zhou, Caihong 1,3,4; Zhou, Yan 3,4; Wang, Jia3,4 ; Feng, Yang 3,4; Wang, Haonan 3,4; Xue, Jinglun 1; Chen, Yani 5; Ye, Richard D.2; Wang, Ming-Wei3,4
刊名	BIOCHEMICAL JOURNAL
	2013-04-15
卷号	451 页码:245-255
关键词	cyclosporin formyl peptide receptor 1 (FPR1) haplotype pharmacogenomics receptor affinity single nucleotide polymorphism
ISSN号	0264-6021
DOI	10.1042/BJ20121839
文献子类	Article
英文摘要	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(alpha 16) 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.
资助项目	Ministry of Science and Technology of China[2009ZX09302-001] ; Ministry of Health[2012ZX09304-011] ; Ministry of Health[2013ZX09507002] ; Chinese Academy of Sciences[SIMM1105KF-03] ; Shanghai Science and Technology Development Fund[10ZR1406900] ; Shanghai Science and Technology Development Fund[11DZ2292200] ; AstraZeneca[00000000] ; CAS-Novo Nordisk Research Fund[00000000]
WOS关键词	N-FORMYLPEPTIDE RECEPTOR ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; AGGRESSIVE PERIODONTITIS ; JUVENILE PERIODONTITIS ; PERSONALIZED MEDICINE ; CHEMOTACTIC AGONIST ; COMBINATION ; DOXORUBICIN ; INHIBITION ; RESPONSES
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	PORTLAND PRESS LTD
WOS记录号	WOS:000317443500012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277652]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Ming-Wei
作者单位	1.Fudan Univ, Inst Genet, Shanghai 200433, Peoples R China; 2.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China 3.Chinese Acad Sci, Natl Ctr Drug Screening, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 5.Shanghai ADICON Clin Labs, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Zhou, Caihong,Zhou, Yan,Wang, Jia,et al. V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins[J]. BIOCHEMICAL JOURNAL,2013,451:245-255.
APA	Zhou, Caihong.,Zhou, Yan.,Wang, Jia.,Feng, Yang.,Wang, Haonan.,...&Wang, Ming-Wei.(2013).V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins.BIOCHEMICAL JOURNAL,451,245-255.
MLA	Zhou, Caihong,et al."V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins".BIOCHEMICAL JOURNAL 451(2013):245-255.