Approarch for neuronal functions of prostaglandins

前列腺素（PGs）对神经元的多种功能具有调节作用，如体温升高和镇痛。此外，研究表明，PG在突触可塑性中发挥重要作用，包括调节神经突起的生长，调节记忆巩固和突触的形成。然而，这些神经元功能的PGs的分子机制还不清楚。在本研究中，我们研究了中枢神经系统中最主要的PGE受体EP 3亚型的细胞内信号转导途径，在PC 12细胞中，EP 3受体诱导神经突起收缩和生长锥塌陷。这种作用是由小GTdR，Rho，及其下游效应，Rho激酶介导的。组成性活性RhoA和Rho激酶诱导神经突起收缩。因此，Rho激酶的激活足以使神经突收缩。我们进一步研究了与EP 3受体偶联的三聚体G蛋白，其与Rho激活途径连接。在各种三聚体G蛋白中，G12、G13和Gq的α亚基通过激活Rho来诱导轴突收缩。然后，我们研究了哪种类型的G蛋白与EP 3受体偶联，并揭示EP 3受体特异性地与G13偶联，导致Rho的激活和神经突收缩的诱导。因此，EP 3受体通过G13-Rho-Rho-激酶途径诱导轴突收缩。EP 3受体的一个众所周知的神经元作用是抑制神经递质释放。然后，我们研究了细胞内信号转导通路的EP 3受体的抑制。在PC 12细胞中，EP 3受体抑制高K或缓激肽诱导的多巴胺释放。G12和G13的组成型活性α亚基和组成型活性RhoA，RhoA-V14也抑制释放。EP 3受体的这种抑制作用是由G13-Rho-Rho-激酶介导的。因此，EP 3受体在神经元形态和突触的调节中起重要作用

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