Approarch for neuronal functions of prostaglandins

前列腺素神经元功能的方法

基本信息

批准号：
10470482
负责人：
NEGISHI Manabu
金额：
$ 8.26万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470482/
关键词：
Prostaglandins Small GTPases Rho Neuron Rho-kinase Trimeric G proteins Receptors Neurite PC12細胞 ROKα ロドプシン

项目摘要

Prostaglandins (PGs) exert a variety of regulations of neuronal functions, such as hyperthermia and analgesia. Furthermore, it has been suggested that PGs play important roles in synaptic plasticity, including regulation of neurite outgrowth, modulation of memory consolidation and formation of synapses. However, molecular mechanisms for these neuronal functions of PGs are not yet understood. In this study, we have examined the intracellular signal transduction pathways of PGE receptor EP3 subtype, the most prominent receptor in CNS.In PC12 cells, EP3 receptor induces neurite retraction and growth cone collapse. This action was mediated by small GTPase, Rho, and its downstream effector, Rho-kinase. Constitutively active RhoA and Rho-kinase induced neurite retraction. Therefore, activation of Rho-kinase is enough for the neurite retraction. We further examined a trimeric G protein coupled to EP3 receptor, linking to the Rho activation pathway. Among various trimericG proteins, α subunits of G12, G13 and Gq induced neurite retraction through the activation of Rho. We then examined which type of G protein was coupled to EP3 receptor, and revealed that EP3 receptor was specifically coupled to G13, leading to activation of Rho and induction of neurite retraction. Therefore, EP3 receptor induces neurite retraction via a G13-Rho-Rho-kinase pathway. One of the well-known neuronal actions of EP3 receptor is the inhibition of neurotransmitter release. We then examined the intracelular signal transduction pathway of EP3 receptor for the inhibition. In PC12 cells, EP3 receptor inhibited the high K-or bradykinin-induced dopamine release. Constitutively active α subunits of G12 and G13 and constitutively active RhoA, RhoA-V14, also inhibited the release. This inhibition by EP3 receptor was mediated by G13-Rho-Rho-kinase. Therefore, EP3 receptor plays an important role in the regulation of neuronal morphology and synaptic

前列腺素（PG）发挥多种神经功能调节作用，例如热疗和镇痛。此外，有人认为PG在突触可塑性中发挥重要作用，包括调节神经突生长、调节记忆巩固和突触形成。 , PGs 的这些神经元功能的分子机制尚不清楚。在这项研究中，我们检查了最突出的 PGE 受体 EP3 亚型的细胞内信号转导途径。在 PC12 细胞中，EP3 受体诱导神经突收缩和生长锥塌陷，这种作用是由小 GTP 酶 Rho 及其下游效应器 Rho 激酶介导的，因此，Rho 激酶诱导神经突收缩。我们进一步研究了与 EP3 受体偶联的三聚体 G 蛋白，该蛋白与 Rho 激活途径相关。各种三聚体G蛋白、G12、G13和Gq的α亚基通过Rho的激活诱导神经突回缩，然后我们检查了哪种类型的G蛋白与EP3受体偶联，并揭示了EP3受体特异性地与G13偶联，导致Rho的激活。 Rho 和神经突收缩的诱导因此，EP3 受体通过 G13-Rho-Rho-激酶途径诱导神经突收缩，这是 EP3 众所周知的神经元作用之一。我们随后检测了EP3受体对PC12细胞内信号转导途径的抑制作用，EP3受体抑制了高K-或缓激肽诱导的G12和G13的组成型活性α亚基的释放。组成型活性 RhoA，RhoA-V14，也抑制 EP3 受体的释放。因此，G13-Rho-Rho-激酶在神经元形态和突触的调节中起着重要作用。