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Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells.

Hisano Y, Kobayashi N, Yamaguchi A, Nishi T - PLoS ONE (2012)

Bottom Line: However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma.Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets.Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan.

ABSTRACT
Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1-5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus.

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Plasma S1P concentration is decreased in SPNS2-deficientmice.(A) Concentration of plasma S1P in wild-type (WT,n = 14) and SPNS2-deficient mice (Δ,n = 9). The P-value fromcomparisons between WT and Δ samples is indicated. (B) Concentrationof whole blood S1P in wild-type (WT, n = 7) andSPNS2-deficient mice (Δ, n = 5). (C) S1Pcontents of mouse tissues. S1P contents of brain, thymus, lung andspleen from wild-type (WT, n = 3) orSPNS2-deficient (Δ, n = 3) mice were measuredby HPLC. C17-S1P was used as the internal standard. Graphsshow the average values from multiple experiments, with error barsrepresenting the standard error. The P-values ofcomparisons between WT and Δ samples is indicated.
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pone-0038941-g003: Plasma S1P concentration is decreased in SPNS2-deficientmice.(A) Concentration of plasma S1P in wild-type (WT,n = 14) and SPNS2-deficient mice (Δ,n = 9). The P-value fromcomparisons between WT and Δ samples is indicated. (B) Concentrationof whole blood S1P in wild-type (WT, n = 7) andSPNS2-deficient mice (Δ, n = 5). (C) S1Pcontents of mouse tissues. S1P contents of brain, thymus, lung andspleen from wild-type (WT, n = 3) orSPNS2-deficient (Δ, n = 3) mice were measuredby HPLC. C17-S1P was used as the internal standard. Graphsshow the average values from multiple experiments, with error barsrepresenting the standard error. The P-values ofcomparisons between WT and Δ samples is indicated.

Mentions: The S1P concentration in the plasma of SPNS2-deficient mice was approximately60% of that observed in wild-type mice, while the S1P concentration inthe whole blood fraction (including blood cells) showed no significantdifference (Figure 3A and3B), suggesting that SPNS2 plays a significant role in maintaining theS1P level in plasma by exporting S1P from S1P-producing cells into the plasma.In various organs (thymus, spleen, lung and brain), the S1P level showed nosignificant differences between wild-type and SPNS2-deficient mice (Figure 3C). Because the S1Pconcentration in these organs reflects the amount of intracellular S1P, weconcluded that SPNS2 does not affect the production or degradation ofintracellular S1P.


Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells.

Hisano Y, Kobayashi N, Yamaguchi A, Nishi T - PLoS ONE (2012)

Plasma S1P concentration is decreased in SPNS2-deficientmice.(A) Concentration of plasma S1P in wild-type (WT,n = 14) and SPNS2-deficient mice (Δ,n = 9). The P-value fromcomparisons between WT and Δ samples is indicated. (B) Concentrationof whole blood S1P in wild-type (WT, n = 7) andSPNS2-deficient mice (Δ, n = 5). (C) S1Pcontents of mouse tissues. S1P contents of brain, thymus, lung andspleen from wild-type (WT, n = 3) orSPNS2-deficient (Δ, n = 3) mice were measuredby HPLC. C17-S1P was used as the internal standard. Graphsshow the average values from multiple experiments, with error barsrepresenting the standard error. The P-values ofcomparisons between WT and Δ samples is indicated.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3379171&req=5

pone-0038941-g003: Plasma S1P concentration is decreased in SPNS2-deficientmice.(A) Concentration of plasma S1P in wild-type (WT,n = 14) and SPNS2-deficient mice (Δ,n = 9). The P-value fromcomparisons between WT and Δ samples is indicated. (B) Concentrationof whole blood S1P in wild-type (WT, n = 7) andSPNS2-deficient mice (Δ, n = 5). (C) S1Pcontents of mouse tissues. S1P contents of brain, thymus, lung andspleen from wild-type (WT, n = 3) orSPNS2-deficient (Δ, n = 3) mice were measuredby HPLC. C17-S1P was used as the internal standard. Graphsshow the average values from multiple experiments, with error barsrepresenting the standard error. The P-values ofcomparisons between WT and Δ samples is indicated.
Mentions: The S1P concentration in the plasma of SPNS2-deficient mice was approximately60% of that observed in wild-type mice, while the S1P concentration inthe whole blood fraction (including blood cells) showed no significantdifference (Figure 3A and3B), suggesting that SPNS2 plays a significant role in maintaining theS1P level in plasma by exporting S1P from S1P-producing cells into the plasma.In various organs (thymus, spleen, lung and brain), the S1P level showed nosignificant differences between wild-type and SPNS2-deficient mice (Figure 3C). Because the S1Pconcentration in these organs reflects the amount of intracellular S1P, weconcluded that SPNS2 does not affect the production or degradation ofintracellular S1P.

Bottom Line: However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma.Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets.Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan.

ABSTRACT
Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1-5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus.

Show MeSH
Related in: MedlinePlus