Physiological implications of biased signaling at histamine H2 receptors.
Physiological implications of biased signaling at histamine H2 receptors.
复制标题
DOI：
10.3389/fphar.2015.00045
复制
发表时间：
2015
影响因子：
5.6
通讯作者：
Fernández NC
中科院分区：
文献类型：
--
作者：
Alonso N;Zappia CD;Cabrera M;Davio CA;Shayo C;Monczor F;Fernández NC
组胺通过其四种受体亚型介导多种功能，所有受体亚型都属于七种跨膜G蛋白偶联受体的大家族。尤其是组胺H2受体（H2 R）主要参与胃酸的产生，成为治疗Zollinger-Ellison病和胃及十二指肠溃疡的经典药理学靶点。H2配体是世界上最广泛使用的处方药和柜台销售的药物之一。最近的证据表明，一些H2 R配体表现出偏向性激动作用，选择并触发一些（但不是全部）与H2 R相关的信号通路。目前的工作的目的是研究法莫替丁，临床广泛使用的配体作用于H2 R，是否施加偏置信号。我们的研究结果表明，虽然法莫替丁作为反向激动剂减少cAMP基础水平，它模仿组胺和激动剂氨甲基苯丙胺有关受体脱敏和内化的影响。此外，用三种配体中的任一种处理HEK 293 T转染的细胞导致浓度依赖性pERK增加。类似地，在AGS胃上皮细胞中，法莫替丁处理导致cAMP水平降低以及ERK磷酸化增加，表明这种行为可能具有药理学相关意义。在此基础上，组氨酸脱羧酶的表达进行了研究，通过定量PCR在AGS细胞和法莫替丁，以及组胺和苯丙胺增加其水平。在所有情况下，正向调节被MEK抑制剂PD 98059阻碍，表明偏向ERK 1/2通路的信号传导是这种酶调节的原因。这些结果支持配体偏好性不仅是药理学上的好奇心，而且对细胞代谢具有生理和药理学意义。
Histamine mediates numerous functions acting through its four receptor subtypes all belonging to the large family of seven transmembrane G-protein coupled receptors. In particular, histamine H2 receptor (H2R) is mainly involved in gastric acid production, becoming a classic pharmacological target to treat Zollinger–Ellison disease and gastric and duodenal ulcers. H2 ligands rank among the most widely prescribed and over the counter-sold drugs in the world. Recent evidence indicate that some H2R ligands display biased agonism, selecting and triggering some, but not all, of the signaling pathways associated to the H2R. The aim of the present work is to study whether famotidine, clinically widespread used ligand acting at H2R, exerts biased signaling. Our findings indicate that while famotidine acts as inverse agonist diminishing cAMP basal levels, it mimics the effects of histamine and the agonist amthamine concerning receptor desensitization and internalization. Moreover, the treatment of HEK293T transfected cells with any of the three ligands lead to a concentration dependent pERK increment. Similarly in AGS gastric epithelial cells, famotidine treatment led to both, the reduction in cAMP levels as well as the increment in ERK phosphorylation, suggesting that this behavior could have pharmacological relevant implications. Based on that, histidine decarboxylase expression was studied by quantitative PCR in AGS cells and its levels were increased by famotidine as well as by histamine and amthamine. In all cases, the positive regulation was impeded by the MEK inhibitor PD98059, indicating that biased signaling toward ERK1/2 pathway is the responsible of such enzyme regulation. These results support that ligand bias is not only a pharmacological curiosity but has physiological and pharmacological implications on cell metabolism.
登录
查看更多内容
影响因子：
4.8
作者：
Ghanouni, P;Gryczynski, Z;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
3.6
作者：
Fernandez, Natalia;Monczor, Federico;Shayo, Carina
通讯作者：
Shayo, Carina
影响因子：
5.8
作者：
Reher, Till M.;Brunskole, Irena;Seifert, Roland
通讯作者：
Seifert, Roland
DOI：
10.1073/pnas.93.13.6802
发表时间：
1996-06-25
影响因子：
11.1
作者：
Smit, MJ;Leurs, R;Timmerman, H
通讯作者：
Timmerman, H
DOI：
10.1073/pnas.0804745105
发表时间：
2008-09-23
影响因子：
11.1
作者：
Kim, Il-Man;Tilley, Douglas G.;Rockman, Howard A.
通讯作者：
Rockman, Howard A.