Gräler Markus H, Goetzl Edward J
University of California, Room UB-8B, UC Box 0711, 533 Parnassus Ave., San Francisco, CA 94143-0711, USA.
FASEB J. 2004 Mar;18(3):551-3. doi: 10.1096/fj.03-0910fje. Epub 2004 Jan 8.
FTY720 is an immunosuppressant that reduces circulating levels of naïve lymphocytes by increasing their localization and sequestration in secondary lymphoid organs. It is considered to be an agonist for sphingosine 1-phosphate (S1P) G protein-coupled receptors (GPCRs) after phosphorylation at micromolar concentrations. We now describe its nonagonist and noncompetitive inhibitory activity at low nanomolar concentrations for types 1 and 5 S1P-GPCRs and of moderate potency for type 2 S1P-GPCRs. FTY720 blocks S1P signaling through S1P1,2,5 by inducing their internalization and intracellular partial degradation without affecting S1P3 or S1P4. S1P-R internalization is maximal several hours after only seconds of incubation with FTY720 at 37 degrees C and washing, and continues for days before recovery of surface expression and functions. The timing and extent of S1P-R internalization are highly dependent on FTY720 concentration. FTY720 is therefore an S1P-GPCR-selective and noncompetitive inhibitor with a unique mechanism of action.
FTY720是一种免疫抑制剂，它通过增加初始淋巴细胞在次级淋巴器官中的定位和滞留来降低其循环水平。在微摩尔浓度下磷酸化后，它被认为是1-磷酸鞘氨醇（S1P）G蛋白偶联受体（GPCR）的激动剂。我们现在描述了它在低纳摩尔浓度下对1型和5型S1P-GPCR具有非激动剂和非竞争性抑制活性，对2型S1P-GPCR具有中等效力。FTY720通过诱导1型、2型和5型S1P-GPCR内化和细胞内部分降解来阻断S1P信号传导，而不影响S1P3或S1P4。在37℃下与FTY720孵育仅数秒并洗涤后，S1P受体内化在数小时后达到最大值，并在表面表达和功能恢复之前持续数天。S1P受体内化的时间和程度高度依赖于FTY720浓度。因此，FTY720是一种具有独特作用机制的S1P-GPCR选择性非竞争性抑制剂。
