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

J Lipid Res. 2014 Dec;55(12):2665-75. doi: 10.1194/jlr.P054163. Epub 2014 Oct 7.

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 (Arg¹²⁰ 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 Gly³⁰⁵ 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.

Keywords: cell signaling; drug therapy; endocytosis; genetics; single nucleotide polymorphism; sphingosine 1-phosphate receptor; sphingosine phosphate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Case-Control Studies
  • Cell Line
  • Cells, Cultured
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Cricetulus
  • Drug Resistance
  • Endocytosis / drug effects*
  • Female
  • Fingolimod Hydrochloride
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Lysophospholipids / metabolism*
  • Male
  • Middle Aged
  • Mutant Proteins / metabolism
  • Polymorphism, Single Nucleotide*
  • Propylene Glycols / pharmacology
  • Receptors, Lysosphingolipid / agonists
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics*
  • Receptors, Lysosphingolipid / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction* / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors

Substances

  • Immunosuppressive Agents
  • Lysophospholipids
  • Mutant Proteins
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • Recombinant Fusion Proteins
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • Fingolimod Hydrochloride
  • Sphingosine