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oai:hama-med.repo.nii.ac.jp:00003067 2023-10-19T01:03:13Z 2:15:17

A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence 正中隆起におけるGABAを介した副腎皮質刺激ホルモン放出ホルモン分泌の新たなメカニズム Kakizawa, Keisuke open access doctoral 医学系研究科 Corticotropin-releasing hormone (CRH), which is synthesized in the paraventricular nucleus (PVN) of the hypothalamus, plays an important role in the endocrine stress response. The excitability of CRH neurons is regulated by γ-aminobutyric acid (GABA)-containing neurons projecting to the PVN. We investigated the role of GABA in the regulation of CRH release. The release of CRH was impaired, accumulating in the cell bodies of CRH neurons in heterozygous GAD67-GFP (green fluorescent protein) knock-in mice (GAD67⁺/GFP), which exhibited decreased GABA content. The GABAA receptor (GABAAR) and the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC1), but not the K⁺-Cl⁻ cotransporter (KCC2), were expressed in the terminals of the CRH neurons at the median eminence (ME). In contrast, CRH neuronal somata were enriched with KCC2 but not with NKCC1. Thus, intracellular Cl⁻ concentrations ([Cl⁻]i) may be increased at the terminals of CRH neurons compared with concentrations in the cell body. Moreover, GABAergic terminals projecting from the arcuate nucleus were present in close proximity to CRH-positive nerve terminals. Furthermore, a GABAAR agonist increased the intracellular calcium (Ca²⁺) levels in the CRH neuron terminals but decreased the Ca²⁺ levels in their somata. In addition, the increases in Ca²⁺ concentrations were prevented by an NKCC1 inhibitor. We propose a novel mechanism by which the excitatory action of GABA maintains a steady-state CRH release from axon terminals in the ME. American Association for the Advancement of Science 2016-08-17 eng doctoral thesis VoR http://hdl.handle.net/10271/3208 https://hama-med.repo.nii.ac.jp/records/3067 27540587 https://doi.org/10.1126/sciadv.1501723 2375-2548 Science Advances 2 8 e1501723 甲第739号 博士（医学） 2016-11-18 13802 浜松医科大学 https://hama-med.repo.nii.ac.jp/record/3067/files/DT_739ronbun.pdf application/pdf 7.2 MB 2018-08-27