Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons.
Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons.
复制标题
DOI：
10.1371/journal.pone.0198024
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Anand P
中科院分区：
文献类型：
--
作者：
Anand U;Yiangou Y;Akbar A;Quick T;MacQuillan A;Fox M;Sinisi M;Korchev YE;Jones B;Bloom SR;Anand P
胰高血糖素样肽1受体（GLP-1 R）激动剂可降低食欲，并可能导致炎症性肠病（IBD）患者体重减轻。本研究的目的是首次确定IBD患者结肠神经纤维的GLP-1 R表达，以及其激动剂在培养的大鼠和人感觉神经元中的功能作用。在IBD患者（n = 16）和对照组（n = 8）的结肠活检组织、人背根神经节（DRG）组织和GLP-1 R转染的HEK 293细胞中，通过免疫组织化学研究了GLP-1 R和其他神经标志物。肠促胰岛素激素胃泌酸调节素，exendin-4和胰高血糖素的形态学效果进行了研究，在培养的DRG神经元的轴突延伸，和辣椒素和ATP信号的功能影响，使用钙成像。在表达GLP-1 R（p = 0.0013）、泛神经元标记物PGP9.5（p = 0.0008）和感觉神经肽CGRP（p = 0.0014）的IBD活检组织中观察到结肠粘膜神经纤维数量显着增加。使用不同的GLP-1 R抗体证实IBD结肠中GLP-1 R阳性神经纤维增加（p = 0.016）。GLP-1 R免疫染色在人DRG的小型和中型神经元以及人和大鼠DRG培养的神经元中呈强阳性。GLP-1 R表达与结肠和DRG中神经元标志物的共定位证实了GLP-1 R的神经表达，并且在用GLP-1 R转染的HEK 293细胞中证实了抗体特异性。与对照组相比，用胃泌酸调节素、exendin-4和GLP-1处理增加了培养的神经元中的神经突长度，但不直接刺激钙内流，也不影响辣椒素反应。然而，exendin-4显著增强人DRG神经元的ATP反应。我们的研究结果表明，在IBD肠GLP-1 R神经支配的增加可以介导增强内脏传入信号，并提供治疗干预的外周靶点。GLP-1 R激动剂对神经元中辣椒素和ATP反应的差异效应表明，它们可能不影响辣椒素受体TRPV 1介导的疼痛机制，但可能增强嘌呤能激动剂的作用。
Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of GLP-1R agonists on capsaicin and ATP responses in neurons suggest they may not affect pain mechanisms mediated by the capsaicin receptor TRPV1, but may enhance the effects of purinergic agonists.
登录
查看更多内容
影响因子：
24.5
作者：
Acosta A;Abu Dayyeh BK;Port JD;Camilleri M
通讯作者：
Camilleri M
影响因子：
4.8
作者：
Dakin, CL;Gunn, I;Bloom, SR
通讯作者：
Bloom, SR
DOI：
10.1152/ajpgi.00076.2012
发表时间：
2012-07-01
影响因子：
4.5
作者：
Camilleri, Michael;Vazquez-Roque, Maria;Zinsmeister, Alan R.
通讯作者：
Zinsmeister, Alan R.
影响因子：
4.9
作者：
Bang-Berthelsen, Claus H.;Holm, Thomas L.;Frederiksen, Klaus S.
通讯作者：
Frederiksen, Klaus S.
影响因子：
25
作者：
Kao, HT;Song, HJ;Greengard, P
通讯作者：
Greengard, P