title: S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.
abstract: HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.
authors.affiliation: Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Appleton
authors.affiliation: Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: El-Shewy
authors.affiliation: Division of Endocrinology, Metabolism, and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC.|Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.affiliation: Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC.|Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC.|Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Luttrell
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Samar M
authors.initials: SM
authors.lastname: Hammad
authors.affiliation: Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC kleinrl@musc.edu.|Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klein
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine; D002118:Calcium
keywords: S1P receptors; high density lipoprotein; protein-fragment complementation assay; scavenger receptor BI; sphingosine 1-phosphate