A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence.
A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence.
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DOI：
10.1126/sciadv.1501723
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发表时间：
2016-08
期刊：
影响因子：
13.6
通讯作者：
Fukuda A
中科院分区：
文献类型：
--
作者：
Kakizawa K;Watanabe M;Mutoh H;Okawa Y;Yamashita M;Yanagawa Y;Itoi K;Suda T;Oki Y;Fukuda A
来自弓状核的兴奋性GABA能输入维持轴突终末的稳态CRH释放，NKCC 1驱动高[Cl−]i。促肾上腺皮质激素释放激素（CRH）是由下丘脑室旁核（PVN）合成，在应激反应中起重要作用。CRH神经元的兴奋性受投射到PVN的γ-氨基丁酸（GABA）神经元的调节。我们研究了GABA在调节CRH释放中的作用。CRH的释放受损，在杂合GAD 67-GFP（绿色荧光蛋白）基因敲入小鼠（GAD 67 +/GFP）的CRH神经元的胞体中积累，表现出GABA含量降低。GABAA受体（GABAAR）和Na+-K+-2Cl−协同转运体（NKCC 1）在正中隆起（ME）的CRH神经元终末表达，但K+-Cl−协同转运体（KCC 2）不表达。相反，CRH神经元胞体富含KCC 2，但不富含NKCC 1。因此，CRH神经元末梢的细胞内Cl−浓度（[Cl−]i）可能比胞体中的浓度高。此外，从弓状核投射的GABA能终末靠近CRH阳性神经终末。此外，GABAAR激动剂增加CRH神经元末梢的细胞内钙（Ca 2+）水平，但降低其胞体中的Ca 2+水平。此外，Ca 2+浓度的增加被NKCC 1抑制剂阻止。我们提出了一种新的机制，GABA的兴奋作用维持了稳态CRH释放轴突终端在ME。
Excitatory GABAergic input from arcuate nucleus maintains steady-state CRH release from axon terminals with NKCC1-driven high [Cl−]i. 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.