Structures and function of prostaglandin E receptors

我们分离了前列腺素（PG） E受体EP1、EP2和EP3三种亚型的cdna，以及EP3三种具有不同cooh末端尾部的亚型EP3， EP3 α、β和γ，它们是通过选择性剪接产生的，对G蛋白偶联的选择性不同。EP1与Gi或Gs以外的未知G蛋白偶联，不依赖于磷脂酶C途径，通过Ca^<2+>-可渗透通道内流Ca^<2+>，激活PKC (protein kinase C， PKC)，抑制肾内Na+离子重吸收。PKC的激活反过来抑制了EP1介导的Ca^<2+>内流，PKC激活的延长下调了EP1 mRNA的水平。因此，PKC不仅是EP1信号的中介，也是EP1的反馈调节器。EP3不仅抑制腺苷酸环化酶，而且通过Gi刺激Ca^<2+>内流。这是由于磷脂酶c - β被Gi释放的β γ亚基激活，从而激活了ip_3响应的Ca^<2+>可渗透通道。PGE_2细胞外Ca^<2+>-依赖性通过EP3诱导子宫收缩。这一作用是由上述机制介导的。原位杂交研究发现，PGE_2在肾细胞的不同片段中有三种亚型的表达，表明PGE_2通过在肾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不同功能的PGE受体亚型和选择性剪接产生的同种异构体的不同表达。

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.