Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator.
Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator.
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Cis-4-methylsphingosine 是一种 1-磷酸鞘氨醇受体调节剂
DOI：
10.1016/j.bcp.2010.12.002
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发表时间：
2011
影响因子：
5.8
通讯作者：
Meyer Zu Heringdorf D
中科院分区：
文献类型：
--
作者：
Ter Braak M;Claas RF;Hegen B;Labocha S;Ferreirós N;Pfeilschifter J;Huwiler A;van Echten-Deckert G;Meyer Zu Heringdorf D
鞘氨醇-1-磷酸(S1P)是特异性G蛋白偶联受体S1P1-5的高亲和力激动剂，在心血管和免疫系统中发挥重要作用。S1P受体调节药物FTY720(Fingolimod)已在多发性硬化症的III期临床试验中有效。FTY720是一种鞘氨醇类似物，也是FTY720-磷酸的前药，它激活除S1P以外的所有S1P受体，并通过内化S1P1受体来干扰淋巴细胞的运输。顺式-4-甲基鞘氨醇(cis-4m-sph)是另一种人工合成的鞘氨醇类似物，很容易被细胞摄取，并被磷酸化为顺式-4-甲基鞘氨醇-1-磷酸(cis-4m-S1P)。因此，我们分析了cis-4m-sph是否通过其代谢产物cis-4m-S1P与S1P受体以类似FTY720的方式相互作用。实际上，cis-4m-sph能内化S1P受体，但与FTY720不同，它作用于S1P和S1P3，仅作用于S1P1，而FTY720内化S1P1和S1P3，但不内化S1P2。因此，cis-4m-sph预孵育可特异性地脱敏S1P诱导的[Ca~(2+)]i升高，这种升高是由S1P和S1P3介导的，且呈时间和浓度依赖性。鞘氨醇或FTY720不具有这种作用，这表明S1P受体的代谢稳定性和靶向性很重要。S1P诱导的[Ca~(2+)]i升高的脱敏作用依赖于SphKs的表达，主要是SphK2的表达，从而由cis-4m-S1P介导。在cis-4m-sph作用的细胞上清液中检测到cis-4m-S1P。结论：cis-4m-sph通过其代谢产物cis-4m-S1P作为S1P受体调节剂，引起S1P受体内化和脱敏。此外，这些数据还有助于确定作为S1P受体调节前体药物的鞘氨醇激酶底物的需求。
Sphingosine-1-phosphate (S1P) acts as high affinity agonist at specific G-protein-coupled receptors, S1P1–5, that play important roles e.g. in the cardiovascular and immune systems. A S1P receptor modulating drug, FTY720 (fingolimod), has been effective in phase III clinical trials for multiple sclerosis. FTY720 is a sphingosine analogue and prodrug of FTY720-phosphate, which activates all S1P receptors except S1P2and disrupts lymphocyte trafficking by internalizing the S1P1receptor. Cis-4-methylsphingosine (cis-4M-Sph) is another synthetic sphingosine analogue that is readily taken up by cells and phosphorylated to cis-4-methylsphingosine-1-phosphate (cis-4M-S1P). Therefore, we analysed whether cis-4M-Sph interacted with S1P receptors through its metabolite cis-4M-S1P in a manner similar to FTY720. Indeed, cis-4M-Sph caused an internalization of S1P receptors, but differed from FTY720 as it acted on S1P2and S1P3and only weakly on S1P1, while FTY720 internalized S1P1and S1P3but not S1P2. Consequently, pre-incubation with cis-4M-Sph specifically desensitized S1P-induced [Ca2+]iincreases, which are mediated by S1P2and S1P3, in a time- and concentration-dependent manner. This effect was not shared by sphingosine or FTY720, indicating that metabolic stability and targeting of S1P2receptors were important. The desensitization of S1P-induced [Ca2+]iincreases was dependent on the expression of SphKs, predominantly of SphK2, and thus mediated by cis-4M-S1P. In agreement, cis-4M-S1P was detected in the supernatants of cells exposed to cis-4M-Sph. It is concluded that cis-4M-Sph, through its metabolite cis-4M-S1P, acts as a S1P receptor modulator and causes S1P receptor internalization and desensitization. The data furthermore help to define requirements for sphingosine kinase substrates as S1P receptor modulating prodrugs.
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1-磷酸盐的出口和功能。
DOI：
10.1016/j.bbalip.2009.02.011
发表时间：
2009-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Kim RH;Takabe K;Milstien S;Spiegel S
通讯作者：
Spiegel S
DOI：
10.1016/s0006-291x(02)02671-2
发表时间：
2002-12-06
影响因子：
3.1
作者：
Osada, M;Yatomi, Y;Ozaki, Y
通讯作者：
Ozaki, Y
磷酸化顺 4-甲基鞘氨醇模拟 1-磷酸鞘氨醇在 Swiss 3T3 成纤维细胞中的促有丝分裂作用*
DOI：
10.1074/jbc.273.36.23585
发表时间：
1998
期刊：
The Journal of Biological Chemistry
影响因子：
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作者：
G. van Echten;Andreas Schick;T. Heinemann;B. Schnieders
通讯作者：
B. Schnieders
影响因子：
3.5
作者：
Heringdorf, DMZ;Liliom, K;Jakobs, KH
通讯作者：
Jakobs, KH
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影响因子：
3.5
作者：
D. Mechtcheriakova;Alexander Wlachos;Jury Sobanov;F. Bornancin;G. Zlabinger;T. Baumruker;A. Billich
通讯作者：
A. Billich