Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions

Abstract

Sphingosine 1-phosphate receptor 1 (S1P 1 ) is a G protein-coupled receptor (GPCR) for a versatile lysophospholipid mediator sphingosine 1-phosphate (S1P) ( 1, 2 ). S1P levels are high in blood and lymph, but low in the interstitial tissue fl uid, thereby forming a gradient important for immune cell traffi cking ( 3 ). S1P, which is poorly soluble in aqueous solutions, is bound by specifi c chaperones. For example, plasma S1P is bound by albumin ( 4 ) or apoM ( 5 ), a specifi c apolipoprotein found in HDL. The S1P-S1P 1 signaling system is critical for sprouting angiogenesis ( 6-8 ) and vascular permeability ( 2, 9-11 ). In addition, part of the vasoprotective, anti-infl ammatory, and anti-atherosclerotic effects associated with HDL is attributed to its cargo, apoM-S1P ( 12-15 ). The S1P-S1P 1 signaling system also plays an important role in immune cell traffi cking ( 3 ). The gradient of S1P concentration between interstitial fl uids and lymph is a basis that allows lymphocytes to egress from secondary lymphoid organs to the circulation via the chemotactic activity of S1P 1 ( 3, 16 ).Previous studies have accumulated signifi cant functional and structural information on S1P 1 ( 1, 2 ). The Abstract 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 neuroinfl ammation. 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 signifi cantly 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 infl uence receptor function and, therefore, infer differential disease risks and interaction with S1P 1 -targeted therapeutics. -Obinata, H., S. Gutkind, J. Stitham, T. Okuno, T. Yokomizo, J. Hwa, and T. Hla. Individual variation of human S1P 1 coding sequence leads to heterogeneity in receptor function and drug interactions. J. Lipid Res. 2014. 55: 2665-2675.

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Recently, Obinata et al (2014) identified several single nucleotide polymorphisms in the S1PR1 gene that influence receptor function. One single nucleotide polymorphism in S1PR1 correlated with a differential coronary artery disease risk, suggesting that genetic variations of S1PR1 may be involved in the pathogenesis of CV diseases.…”

Collaborative Cross Mice Yield Genetic Modifiers for Pseudomonas aeruginosa Infection in Human Lung Disease

“…S1P1 is expressed in a variety of cell types, including endothelial and epithelial cells, T cells, natural killer T cells, innate lymphoid cells, and dendritic cells (26,34,35). In humans, 15 nonsynonymous S1PR1 SNPs have been identified by the U.S. National Heart, Lung, and Blood Institute Exome Sequencing Project (36). Functional variants have been associated with asthma susceptibility, constituting a risk factor for disease severity (37), which supports the idea that genetic variants of S1PR1 may influence physiological and pathological events in the lung compartment.…”

Deletion of Sphingosine 1-Phosphate Receptor 1 in cardiomyocytes during development leads to abnormal ventricular conduction and fibrosis

“…Furthermore, significantly fewer S1PR1 missense variants were observed in gnomAD than expected (232 missense variants expected, 120 observed missense variants, z = 2.61). Finally, missense variants identified in the NHLBI Exome Sequencing Project have been functionally assessed: the Arg120Pro variant (rs149198314; identified in 1/13,005 alleles) failed to activate S1P1 signaling or internalization in response to S1P, and Arg120 was found to be critical for S1P binding [41][42][43]. Hence, individuals who are heterozygous for predicted loss-of-function S1PR1 alleles have been observed at very low frequency, and cardiomyopathy exome/genome sequencing studies may reveal additional S1PR1 variants that disrupt S1P1 function.…”