MOLECULAR APPROACHES FOR FUNCTIONS AND PHYSIOLOGICAL SIGNIFICANCE OF PROSTAGLANDIN E RECEPTORS

前列腺素 E 受体功能和生理意义的分子方法

基本信息

批准号：
07672353
负责人：
NEGISHI Manabu
金额：
$ 1.66万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672353/
关键词：
PROSTAGLANDINE2 SUBTYPE ISOFORM DESENSITIZATION NEURITE RETRACTION RHO G蛋白質中枢神経系 Gi活性

项目摘要

We previously identified three isoforms of the mouse prostaglandin (PG) E receptor EP3 subtype, EP3alpha, EP3beta and EP3gamma, with different COOH-terminal tails, produced through alternative splicing. We examined the Gi activities of these isoforms. The EP3alpha receptor showed marked agonist-independent constitutive Gi activity, the EP3beta receptor had no constitutive activity, and the EP3gamma receptor showed mostly full constitutive activity. Thus, the EP3 receptor isoforms differ in constitutive Gi activity.Among four PGE receptor subtypes, the EP2 and EP4 receptors are coupled to the same signal transduction pathway, stimulation of adenylate cyclase. However, the EP4 receptor underwent short term agonist-induced desensitization, but no such desensitization was observed for the EP2 receptor. On the other hand, PGE_2 is rapidly metabolized to 15-keto-PGE_2. The EP4 receptor markedly lost the response for the metabolite, but the EP2 receptor still had significant response. Therefore, the physiological significance of EP2 and EP4 receptors may lie in their different sensitivities to agonist-induced short term desensitization and their differential susceptibilities to the metabolic inactivation of the agonist.The EP3 receptor is widely distributed in the nervous system and is specifically localized to neurons. when the EP3 receptor was expressed in PC-12 cells, in the differentiated cells, an EP3 agonist caused neurite retraction in a pertussis toxin-insensitive manner. C3 exoenzyme completely inhibited the EP3 agonist-induced neurite retraction when microinjected into the cells, indicating that the morphological effect of the EP3 receptor is dependent on Rho activity.

我们先前鉴定出三种小鼠前列腺素（PG）E受体EP3亚型，Ep3alpha，Ep3beta和Ep3gamma，具有不同的COOH末端尾巴，通过替代剪接产生。我们检查了这些同工型的GI活性。 Ep3alpha受体显示出明显的依赖激动剂的本构胃肠道活性，EP3BETA受体没有组成活性，Ep3gamma受体大多显示出完全的本构活性。因此，EP3受体同工型在组成式GI活性上有所不同。在四个PGE受体亚型中，EP2和EP4受体耦合到相同的信号转导途径，刺激腺苷酸环化酶。但是，EP4受体经历了短期激动剂诱导的脱敏，但是对于EP2受体没有观察到这种脱敏。另一方面，PGE_2迅速将其代谢为15-Keto-PGE_2。 EP4受体显着失去了代谢产物的反应，但是EP2受体仍然具有显着的反应。因此，EP2和EP4受体的生理意义可能在于它们对激动剂诱导的短期脱敏的敏感性及其对激动剂的代谢失活的差异敏感性。EP3受体广泛分布在神经系统中，并专门局限于神经元。当在分化细胞中在PC-12细胞中表达EP3受体时，EP3激动剂以百日咳毒素不敏感的方式引起神经突收缩。当微分注射到细胞中时，C3外酶完全抑制了EP3激动剂诱导的神经突收缩，表明EP3受体的形态效应取决于RHO活性。