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.

我们有三种亚型的前列腺素（PG）E受体，EP1，EP2和EP3的cDNA，以及具有不同COOH末端尾巴的EP3，EP3Alpha，beta和Gamma的三种EP3的同工型，它们是通过替代拼接产生的，并且在G蛋白偶联的选择性上产生。除GI或GS以外，EP1与未知的G蛋白偶联，并通过CA^<2+>涌入CA^<2+> - 可渗透通道独立于磷脂酶C途径，从而激活蛋白激酶C（PKC）并抑制Na+ion ion Recebortion na+ion reabstigntion。 PKC的激活反过来抑制了EP1介导的Ca^<2+>涌入，并且长时间的PKC激活下调了EP1 mRNA的水平。PKC不仅是EP1信号的介体，而且是EP1.EP1的反馈调节剂。EP3不仅抑制腺苷酸环酶，还刺激了Ca^<2 <2 <2 <2> fiff gi> impert gi> gi> gi。这是由于IP_3响应Ca^<2+>可渗透通道的激活，这是由于磷脂酶C-beta激活了从GI释放的Betagamma亚基引起的。 PGE_2细胞外Ca^<2+> - 相关地诱导子宫通过EP3的收缩。该动作是由上述机制介导的。原始杂交研究表明，三种亚型在肾单位的不同段中表达，这表明PGE_2通过在不同肾脏区域表达的这些亚型发挥多种功能。细胞对PGE_2在PGE_2中的多样性主要基于通过祭坛剪接产生的功能不同的PGE受体亚型和同工型的不同表达。