| Co-Investigator(Kenkyū-buntansha) |
SUGIMOTO Yukihiko Kyoto University Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (80243038)
UEZONO Yasuhito Nagasaki University School of Medicipfe, Lecturer, 医学部, 講師 (20213340)
UETA Yoichi University of Occupational and Environmental Health, School of Medicine, Professor, 医学部, 教授 (10232745)
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| Research Abstract |
5) Astrocytes PGE_2, PGD_2, PGF_<2a>, but neither IPagonist U-46619 nor TP agonist carbacyclin, induced a rise in [Ca??], in cultured rat astrocytes. RT-PCR analysis of astrocytes revealed all known 8 PG receptor mRNAs. These multiple PG receptors may be involved in signal transduction via PGs in the CNS.
To elicidate the precise cellular and molecular mechanisms involved in the prostaglandin (PG)-mediated regulation of neuronal and endocrine cells, we have examined membrane potentials, membrane currents, cytosolic Ca^<2+> concentration ([Ca^<2+>]) and mRNAs in several types of cells.
1) Supraoptic nucleus (SON) neurons PGE_2 and PGF_<2a> caused an increase in the action potential discharge, cationic currents, somatodendritic release of oxytocin and vasopressin and in [Ca^<2+>]. These effects were mimicked by the selective EP_4 agonist ONO-AE1-329 and the FP agonist fluprostenol, while EP_1 agonist ONQ-DI-004, EP_2 agonist ONO-AE1-257 and EP_3 agonist ONO-AE-248 had little effect. PGE_2
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but not PGF_<2a> reduced the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) without affecting the amplitude. This was mimicked by the EP_3 agonist but other three selective EPagonist had little effect. These results indicate that PG receptors are present both at the pre- and post-synaptic sites of SON neurons : postsynaptic EP_4 and FP receptors are coupled to non-selective cation channels, activation of which results in membrane depolarization and Ca^<2+> entry through voltage-gated Ca^<2+> channels ; and presynaptic EP_3 receptors in GABA neurons suppress GABA release, which results in disinhibition of SON neurons. These multiple excitatory mechanisms mediated by pre- and postsynaptic PG receptors may play important roles in the regulation of SON neurons by PGs.
2) Adrenal chromaffin cells PGE_2 and ONO-DI-004 induced Ca?? release and Ca?? entry in cultured bovine adrenal chromaffin cells. RT-PCR analysis revealed that the adrenal medulla of rats express EP_1, EP_3, EP_4 receptor mRNAs, suggesting a role of EP1receptors in the chromaffin cells.
3) Melanotrophs of the pituitary pars intermedia PGE_2, and ONO-AE-248 caused a reduction in [Ca^<2+>]. PGE_2 suppressed voltage-gated Ca^<2+> channel currents, but had little effect on inwardly rectifying K^+ currents. EP_3 receptor mRNA was detected in the pars intermedia tissue, suggesting EP_3 receptors are selectively coupled with voltage-gated Ca^<2+> channels.
4) Dorsal root ganglion (DRG) neurons PGE_2, ONO-AE1-257 and ONO-AE1-328 induced a rise in [Ca^<2+>], in capsaicin-sensitive mouse DRG neurons, indicating EP_2 and EP_4 receptors are involved in nociception.
6) Whole-animal experiments with mice Intracerebroventricular injection of any of the four selective EPagonists had little effect on drinking and other behaviors. Less
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