NDLI: Individual variation of human $S1P_{1}$ coding sequence leads to heterogeneity in receptor function and drug interactions

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Obinata, Hideru Gutkind, Sarah Stitham, Jeremiah Okuno, Toshiaki Yokomizo, Takehiko Hwa, John Hla, Timothy
Description	Author Affiliation: Obinata H ( Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.); Gutkind S ( Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.); Stitham J ( Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.); Okuno T ( Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.); Yokomizo T ( Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.); Hwa J ( Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.); Hla T ( Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.)
Abstract	Sphingosine 1-phosphate receptor 1 (S1P1), 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 S1P1 receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P1 receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P1 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 (Arg¹²° 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 (Ile45 to Thr and Gly³°5 to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg¹³ 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 S1P1 can influence receptor function and, therefore, infer differential disease risks and interaction with S1P1-targeted therapeutics.
File Format	HTM / HTML
ISSN	00222275
e-ISSN	15397262
DOI	10.1194/jlr.P054163
Journal	The Journal of Lipid Research
Issue Number	12
Volume Number	55
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Coronary Artery Disease Genetics Endocytosis Drug Effects Immunosuppressive Agents Pharmacology Lysophospholipids Metabolism Polymorphism, Single Nucleotide Receptors, Lysosphingolipid Signal Transduction Sphingosine Analogs & Derivatives Animals Case-control Studies Cell Line Cells, Cultured Cricetulus Drug Resistance Fingolimod Hydrochloride Genetic Association Studies Genetic Predisposition To Disease Mutant Proteins Propylene Glycols Agonists Antagonists & Inhibitors Recombinant Fusion Proteins Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Endocrinology

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