Evidence for ligand-specific conformations of the histamine H2-receptor in human eosinophils and neutrophils
Evidence for ligand-specific conformations of the histamine H2-receptor in human eosinophils and neutrophils
复制标题
DOI：
10.1016/j.bcp.2012.08.014
复制
发表时间：
2012-11-01
影响因子：
5.8
通讯作者：
Seifert, Roland
中科院分区：
文献类型：
--
作者：
Reher, Till M.;Brunskole, Irena;Seifert, Roland
组胺 H-2 受体 (H2R) 与 G(s) 蛋白偶联并诱导腺苷酸环化酶介导的 cAMP 积累。在人中性粒细胞和嗜酸性粒细胞中，H2R 减少趋化肽刺激的超氧阴离子 (O-2(-)) 形成。然而，这些细胞中 H2R 的药理学特征还远未完成。本研究的目的是提供中性粒细胞和嗜酸性粒细胞中 H2R 的全面分析。组胺抑制人中性粒细胞中 O-2(-) 的形成比嗜酸性粒细胞更有效。 H2R 激动剂模仿组胺的作用，而 H2R 拮抗剂则阻断组胺的作用。我们注意到 H2R 激动剂在两种细胞类型中 cAMP 积累和 O-2(-) 形成抑制方面的效力和功效存在多种差异。 cAMP 积累和中性粒细胞中 O-2(-) 形成抑制之间的拮抗剂谱也存在差异。此外，重组 H2R 的药理学特性与天然细胞中的 H2R 特性不匹配。在人类中性粒细胞中鉴定的 H2R 序列与已发表的 H2R 序列相对应，但不包括作为差异解释的新 H2R 亚型的排他性表达。配体之间的差异很可能是通过具有独特亲和力、效力和功效的配体特异性受体构象的存在来解释的。因此，我们的数据为配体特异性受体构象的概念可以从重组系统扩展到天然细胞的概念提供了证据。 (c) 2012 Elsevier Inc. 保留所有权利。
The histamine H-2-receptor (H2R) couples to G(s)-proteins and induces adenylyl cyclase-mediated cAMP accumulation. In human neutrophils and eosinophils, the H2R reduces chemotactic peptide-stimulated superoxide anion (O-2(-)) formation. However, pharmacological characterization of the H2R in these cells is far from being complete. The aim of this study was to provide a comprehensive profiling of the H2R in neutrophils and eosinophils. Histamine inhibited O-2(-) formation in human neutrophils more effectively than in eosinophils. H2R agonists mimicked the effects of histamine and H2R antagonists blocked the effects of histamine. We noticed multiple discrepancies in the potencies and efficacies of H2R agonists with respect to cAMP accumulation and inhibition of O-2(-) formation in both cell types. There were also differences in the antagonist profiles between cAMP accumulation and inhibition of O-2(-) formation in neutrophils. Moreover, the pharmacological profile of the recombinant H2R did not match the H2R profile in native cells. The H2R sequence identified in human neutrophils corresponds to the published H2R sequence, excluding the exclusive expression of a new H2R isoform as explanation for the differences. Very likely, the differences between ligands are explained by the existence of ligand-specific receptor conformations with unique affinities, potencies and efficacies. Thus, our data provide evidence for the notion that the concept of ligand-specific receptor conformations can be extended from recombinant systems to native cells. (c) 2012 Elsevier Inc. All rights reserved.