The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion
The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion
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DOI：
10.1152/ajpgi.00087.2011
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发表时间：
2012-02-01
影响因子：
4.5
通讯作者：
Kidd, M.
中科院分区：
文献类型：
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作者：
Chin, A.;Svejda, B.;Kidd, M.
Chin A，Svejda B，Gustafsson BI，Granlund AB，Sandvik AK，Timberlake A，Sumpio B，Pfragner R，Modlin IM，Kidd M.机械力和腺苷在调节肠嗜铬细胞5-羟色胺分泌中的作用。美国生理学杂志胃肠和肝脏生理学302：G397-G405，2012年。首次发表于2011年10月28日; doi：10.1152/ajpgi.00087.2011。弥漫性神经内分泌细胞系统的肠嗜铬（EC）细胞分泌5-羟色胺（5-HT），激活肠道运动、分泌和疼痛。这些细胞表达腺苷（ADORA）受体，被认为是机械传感器。介导机械敏感性和腺苷反应性的生理途径仍有待充分阐明，它们在炎症性肠病（IBD）和肿瘤形成中的作用也是如此。研究了纯的（98-99%）FACS分选的正常和IBD人EC细胞和肿瘤EC细胞（KRJ-I）。IBD-EC细胞和KRJ-I过表达AD 0 RA 2B。一般ADORA受体激动剂NECA刺激5-HT释放，而A2 B受体拮抗剂MRS 1754抑制5-HT释放（EC 50 = 1.8 x 10（-6）M; IC 50 = 3.7 x 10（-8）M），这与细胞内cAMP水平和pCREB（Ser 133）的相应变化有关。机械刺激诱导色氨酸羟化酶（Tph 1）和囊泡单胺转运体1（VMAT（1））的转录和激活以及5-HT的释放，MRS 1754可抑制这些转录和激活，NECA可放大这些转录和激活。H-89（PKA抑制剂）也能抑制分泌，而Tph 1和VMAT（1）的转录受PKA/MAPK和PI 3 K介导的信号调节。正常和IBD-EC细胞也响应NECA和机械刺激PKA活化，cAMP产生和5-HT释放，MRS 1754可逆的影响。EC细胞表达刺激性ADORA 2B，节律性牵张诱导A2 B活化、PKA/MAPK/IP 3依赖性转录和PKA依赖性分泌5-HT合成和分泌。在IBD和肿瘤中受体表达增强，5-HT释放增加。确定调节EC细胞功能的因素对于理解其作为机械感觉细胞的作用和促进能够选择性靶向EC细胞相关疾病中的细胞功能的试剂的开发是必要的。
Chin A, Svejda B, Gustafsson BI, Granlund AB, Sandvik AK, Timberlake A, Sumpio B, Pfragner R, Modlin IM, Kidd M. The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion. Am J Physiol Gastrointest Liver Physiol 302: G397-G405, 2012. First published October 28, 2011; doi:10.1152/ajpgi.00087.2011.-Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 x 10(-6) M; IC50 = 3.7 x 10(-8) M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT(1) (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT(1) transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.