Structures and function of prostaglandin E receptors

前列腺素E受体的结构和功能

基本信息

批准号：
05671816
负责人：
NEGISHI Manabu
金额：
$ 1.41万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

We have isolated cDNAs for three subtypes of prostaglandin (PG) E receptor, EP1, EP2 and EP3, and three isoforms of EP3 with different COOH-terminal tails, EP3alpha, beta and gamma, which are produced through alternative splicing and differ in selectivity of G protein coupling. EP1 is coupled to unknown G protein other than Gi or Gs, and exerts Ca^<2+> influx through Ca^<2+>-permeable channel independent of phospholipase C pathway, resulting in activation of protein kinase C (PKC) and inhibition of Na+ ion reabsorption in kidney. The activation of PKC in turn suppressed the EP1-mediated Ca^<2+> influx, and prolonged PKC activation down-regulated the level of EP1 mRNA.Thus, PKC is not only a mediator of EP1 signals but also a feedback regulator of EP1.EP3 not only inhibited adenylate cyclase but also stimulated Ca^<2+> influx via Gi. This is due to activation of IP_3-responsive Ca^<2+> permeable channel, resulting from phospholipase C-beta activation by betagamma subunits released from Gi. PGE_2 extracellular Ca^<2+>-dependently induces contraction of uterus through EP3. This action is mediated by the mechanism mentioned above.In situ hybridization studies have revealed that three subtypes are expressed in different segments of the nephron, suggesting that PGE_2 exerts multiple functions via these subtypes expressed in different kidney regions. The diversity of the cellular responses to PGE_2 in mainly based on the different expression of functionally different PGE receptor subtypes and isoforms produced through altarnative splicing.

我们分离了前列腺素 (PG) E 受体三种亚型 EP1、EP2 和 EP3 的 cDNA，以及具有不同 COOH 末端尾部的 EP3 三种亚型 EP3α、β 和 γ，它们是通过选择性剪接产生的，并且选择性剪接不同G蛋白偶联。 EP1与除Gi或Gs之外的未知G蛋白偶联，并通过独立于磷脂酶C途径的Ca^2+通透通道发挥Ca^2+流入，导致蛋白激酶C(PKC)的激活和抑制肾脏对Na+离子的重吸收。 PKC的激活反过来抑制了EP1介导的Ca^2+内流，并且延长的PKC激活下调了EP1 mRNA的水平。因此，PKC不仅是EP1信号的介质，而且是EP1的反馈调节器EP3不仅抑制腺苷酸环化酶，而且还刺激Ca 2+ 通过Gi流入。这是由于IP_3响应性Ca ^ 2+ 渗透通道的激活，其是由Gi释放的βγ亚基激活磷脂酶C-β引起的。 PGE_2细胞外Ca 2+ 依赖性地通过EP3诱导子宫收缩。这一作用是通过上述机制介导的。原位杂交研究表明，三种亚型在肾单位的不同部位表达，表明PGE_2通过在肾脏不同区域表达的这些亚型发挥多种功能。细胞对PGE_2反应的多样性主要基于功能不同的PGE受体亚型和通过选择性剪接产生的亚型的不同表达。