期刊
JOURNAL OF LIPID RESEARCH
卷 55, 期 12, 页码 2665-2675出版社
ELSEVIER
DOI: 10.1194/jlr.P054163
关键词
sphingosine phosphate; drug therapy; cell signaling; endocytosis; genetics; sphingosine 1-phosphate receptor; single nucleotide polymorphism
资金
- National Institutes of Health [HL89934, HL117798]
- National Heart, Lung, and Blood Institute [HL102923]
- WHI Sequencing Project [HL102924]
- Broad GO Sequencing Project [HL102925]
- Seattle GO Sequencing Project [HL102926]
- Heart GO Sequencing Project [HL103010]
- Grants-in-Aid for Scientific Research [22116001, 25460374, 22116002] Funding Source: KAKEN
Sphingosine 1-phosphate receptor 1 (S1P(1)), an abundantly-expressed G protein-coupled receptor which regulates key vascular and immune responses, is a therapeutic target in autoimmune diseases. Fingolimod/Gilenya (FTY720), an oral medication for relapsing-remitting multiple sclerosis, targets S1P(1) receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P(1) receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P(1) coding region from exon sequencing of >12,000 individuals and their functional consequences. We conducted functional analyses of 14 nonsynonymous single nucleotide polymorphisms (SNPs) of the S1PR1 gene. One SNP mutant (Arg(120) to Pro) failed to transmit sphingosine 1-phosphate (S1P)-induced intracellular signals such as calcium increase and activation of p44/42 MAPK and Akt. Two other mutants (Ile(45) to Thr and Gly(305) to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg(13) to Gly) demonstrated protection from coronary artery disease in a high cardiovascular risk population. Individuals with this mutation showed a significantly lower percentage of multi-vessel coronary obstruction in a risk factor-matched case-control study. This study suggests that individual genetic variations of S1P(1) can influence receptor function and, therefore, infer differential disease risks and interaction with S1P(1)-targeted therapeutics.
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