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首页> 美国卫生研究院文献>Endocrinology >Activation of Type 1 CRH Receptor Isoforms Induces Serotonin Release from Human Carcinoid BON-1N Cells: An Enterochromaffin Cell Model
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Activation of Type 1 CRH Receptor Isoforms Induces Serotonin Release from Human Carcinoid BON-1N Cells: An Enterochromaffin Cell Model

机译：1型CRH受体亚型的激活诱导人类类癌BON-1N细胞释放5-羟色胺：一种肠嗜铬细胞模型

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CRH and 5-hydroxytryptamine (5-HT) are expressed in human colonic enterochromaffin (EC) cells, but their interactions at the cellular level remain largely unknown. The mechanistic and functional relationship between CRH and 5-HT systems in EC cells was investigated in a human carcinoid cloned BON cell line (BON-1N), widely used as an in vitro model of EC cell function. First, we identified multiple CRH1 splice variants, including CRH1a, CRH1c, CRH1f, and a novel form lacking exon 4, designated here as CRH1i, in the BON-1N cells. The expression of CRH1i was also confirmed in human brain cortex, pituitary gland, and ileum. Immunocytochemistry and immunoblot analysis confirmed that BON-1N cells were CRH1 and 5-HT positive. CRH, urocortin (Ucn)-1, and cortagine, a selective CRH1 agonist, all increased intracellular cAMP, and this concentration-dependent response was inhibited by CRH1-selective antagonist NBI-35965. CRH and Ucn-1, but not Ucn-2, stimulated significant ERK1/2 phosphorylation. In transfected human embryonic kidney-293 cells, CRH1i isoforms produced a significant increase in pERK1/2 in response to CRH1 agonists that was sensitive to NBI-35965. CRH and Ucn-1 stimulated 5-HT release that reached a maximal increase of 3.3- and 4-fold at 10−8m over the basal level, respectively. In addition, exposure to CRH for 24-h up-regulated tryptophan hydroxylase-1 mRNA levels in the BON-1N cells. These findings define the expression of EC cell-specific CRH1 isoforms and activation of CRH1-dependent pathways leading to 5-HT release and synthesis; thus, providing functional evidence of a link exists between CRH and 5-HT systems, which have implications in stress-induced CRH1 and 5-HT-mediated stimulation of lower intestinal function.
机译：CRH和5-羟色胺（5-HT）在人结肠肠嗜铬细胞（EC）细胞中表达，但它们在细胞水平上的相互作用仍然未知。在人类类癌克隆的BON细胞系（BON-1N）中研究了EC细胞中CRH和5-HT系统之间的机制和功能关系，该细胞系广泛用作EC细胞功能的体外模型。首先，我们在BON-1N细胞中鉴定了多个CRH1剪接变体，包括CRH1a，CRH1c，CRH1f和缺少外显子4的新型形式，此处称为CRH1i。在人的大脑皮层，垂体和回肠中也证实了CRH1i的表达。免疫细胞化学和免疫印迹分析证实BON-1N细胞为CRH1和5-HT阳性。 CRH，尿皮质素（Ucn）-1和可卡汀（一种选择性的CRH1激动剂）均增加了细胞内cAMP，并且这种浓度依赖性反应被CRH1选择性拮抗剂NBI-35965抑制。 CRH和Ucn-1（而非Ucn-2）刺激了显着的ERK1 / 2磷酸化。在转染的人类胚胎肾-293细胞中，CRH1i同工型响应对NBI-35965敏感的CRH1激动剂，使pERK1 / 2显着增加。 CRH和Ucn-1刺激了5-HT的释放，在基础水平的10 -8 m处分别达到了3.3倍和4倍的最大增加。此外，暴露于CRH中24小时可上调BON-1N细胞中的色氨酸羟化酶-1 mRNA水平。这些发现定义了EC细胞特异性CRH1亚型的表达以及导致5-HT释放和合成的CRH1依赖性途径的激活。因此，提供了CRH和5-HT系统之间存在联系的功能证据，这对应激诱导的CRH1和5-HT介导的肠道功能降低有影响。

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