Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
Biochem Pharmacol. 2014 Nov 15;92(2):369-79. doi: 10.1016/j.bcp.2014.08.028. Epub 2014 Sep 6.
Histamine receptors are G-protein-coupled receptors (GPCRs). Canonically, the histamine H2-receptor (H2R) couples to Gs-proteins and activates adenylyl cyclases (ACs) with subsequent adenosine-3',5'-cyclic monophosphate (cAMP) generation. Recently, the classic two-state model describing GPCR activation has been extended to a multiple-state model implying that any ligand stabilizes a ligand-specific receptor conformation, also referred to as functional selectivity. In our present study we pharmacologically characterized the H2R in human monocytes. We found dissociations in the effects of histamine (HA) and H2R agonists on cAMP accumulation and inhibition of formyl peptide-induced production of reactive oxygen species (ROS). In addition, we excluded participation of protein kinase A (PKA) in HA-induced ROS inhibition. Comparison of the potencies and efficacies of H2R agonists in monocytes, neutrophils and eosinophils unmasked cell type-specific pharmacological profiles of individual ligands. Taken together, our data extend the concept of functional selectivity to the H2R in human monocytes and demonstrate striking cell-type specificity in the pharmacological profile of the H2R.
组胺受体是 G 蛋白偶联受体（GPCRs）。通常，组胺 H2 受体（H2R）与 Gs 蛋白偶联并激活腺苷酸环化酶（AC），随后产生环磷酸腺苷（cAMP）。最近，描述 GPCR 激活的经典两态模型已扩展为多态模型，表明任何配体都能稳定配体特异性受体构象，也称为功能选择性。在本研究中，我们对人单核细胞中的 H2R 进行了药理学表征。我们发现组胺（HA）和 H2R 激动剂对 cAMP 积累和抑制甲酰肽诱导的活性氧（ROS）产生的影响存在差异。此外，我们排除了蛋白激酶 A（PKA）参与 HA 诱导的 ROS 抑制。在单核细胞、中性粒细胞和嗜酸性粒细胞中比较 H2R 激动剂的效价和效能，揭示了单个配体的细胞类型特异性药理学特征。总之，我们的数据将功能选择性的概念扩展到人类单核细胞中的 H2R，并证明 H2R 的药理学特征具有显著的细胞类型特异性。
