Molekulare Mechanismen der ligandenselektiven Aktivierung unterschiedlicher Signaltransduktionswege am Beispiel des Histamin-H1-Rezeptors

g蛋白偶联受体可能是最重要的细胞表面受体，负责大量的生理功能，如视觉接收、嗅觉、味觉、炎症反应和神经传递。最初的理论表明，这些受体只与一种g蛋白偶联，g蛋白信号可以被激动剂激活，被拮抗剂抑制。然而，最近的证据表明，这种描述过于简单化了。许多g蛋白偶联受体参与多种类型的g蛋白，导致配体选择性激动作用现象，这描述了激动剂区分不同g蛋白信号通路的能力。大量g蛋白偶联受体（包括组胺H1受体）存在混杂的g蛋白偶联和配体选择性激动作用。刺激H1受体可通过激活Gq/11蛋白导致过敏样症状，如鼻炎、哮喘、过敏反应和荨麻疹，而在中枢神经系统中发现了gs蛋白的激活。选择性激活gs蛋白通路而无过敏样副作用的药物的开发可能成为中枢神经疾病治疗的新途径。因此，本项目旨在研究H1受体的配体选择性激动作用的分子机制，为开发有前景的新型信号转导途径选择性H1受体激动剂奠定基础。

G-protein-coupled receptors probably are the most important cell surface receptors responsible for a large number of physiological functions like visual reception, smell, taste, inflammatory response, and neurotransmission. Initial theories suggested that these receptors are coupled to only one type of G-proteins and G-protein signaling can be activated by agonists and inhibited by antagonists. However, recent evidence suggests that this description is an oversimplification. Many G-protein-coupled receptors engage more than one type of G-proteins leading to the phenomenon of ligand-selective agonism, which describes the ability of an agonist to discriminate between different G-protein signaling pathways. Promiscuous G-protein coupling and ligand-selective agonism has been found for a large number of G-protein-coupled receptors, including histamine H1 receptors. Stimulation of H1 receptors leads to allergy-like symptoms like rhinitis, asthma, anaphylaxis, and urticaria via an activation of Gq/11-proteins, whereas an activation of Gsproteins has been found in the central nervous system. The development of drugs which selectively activate the Gs-protein pathway and therefore lack of allergy-like side-effects may become new avenues in the therapy of central nervous disorders. Thus, this project is aimed to investigate the molecular mechanisms of the ligand-selective agonism at H1 receptors, which are the basis for the development of promising new signal transduction pathway-selective H1 receptor agonists.