Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate
Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate
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DOI：
10.1074/jbc.m311743200
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发表时间：
2004-04-02
影响因子：
4.8
通讯作者：
Rosen, H
中科院分区：
文献类型：
--
作者：
Sanna, MG;Liao, JY;Rosen, H
1-磷酸鞘氨醇（S1 P）通过五种相关的高亲和力G蛋白偶联受体影响心率、冠状动脉口径、内皮完整性和淋巴细胞再循环。非选择性S1 P受体激动剂抑制淋巴细胞再循环可产生临床免疫抑制，预防移植排斥反应，但与一过性心动过缓相关。由于S1 P（1）基因敲除的胚胎致死性和选择性激动剂或拮抗剂的不可用，对单个受体作用的理解受到限制。发现一种结构上与S1 P无关的强效S1 P（1）受体选择性激动剂可激活S1 P触发的多种信号，包括鸟苷5 '-3-O-（硫代）三磷酸结合、钙流、Akt和ERK 1/2磷酸化，以及刺激体外表达S1 P（1）而非S1 P（3）的细胞迁移。该激动剂还改变体内淋巴细胞运输。选择性激动剂与缺乏S1 P（3）受体的缺失小鼠一起使用表明，单独激动S1 P（1）受体足以控制淋巴细胞再循环。此外，S1 P（1）受体激动剂血浆水平与淋巴细胞减少症的诱导和维持存在因果关系。S1 P（3），而不是S1 P（1），直接涉及窦性心动过缓。野生型小鼠中由S1 P受体非选择性免疫抑制激动剂诱导的持续性心动过缓在S1 P（3）（-/-）小鼠中消失，而S1 P（1）选择性激动剂不产生心动过缓。分离用于控制淋巴细胞再循环和心率的受体亚型可能允许鉴定具有增强的治疗窗的选择性免疫抑制性S1 P（1）受体激动剂。S1 P（1）选择性激动剂将在体外理解细胞功能和体内血管生理学方面具有广泛的用途，S1 P（1）化学方法的成功表明，现在可以通过选择性工具来解决这个广泛的脂质受体家族的功能。
Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P(1) knock-out and the unavailability of selective agonists or antagonists. A potent, S1P(1)-receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5'-3-O-( thio) triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P(1)- but not S1P(3)-expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P(3) receptor reveals that agonism of S1P(1) receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P(1) receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P(3), and not S1P(1), is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor nonselective immunosuppressive agonists in wild-type mice is abolished in S1P(3)(-/-) mice, whereas S1P(1)-selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P(1) receptor agonists with an enhanced therapeutic window. S1P(1)- selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P(1) suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.