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，负责许多生理功能，如视觉接收，嗅觉，味觉，炎症反应和神经传递。最初的理论认为这些受体仅与一种类型的G蛋白偶联，并且G蛋白信号可以被激动剂激活并被拮抗剂抑制。然而，最近的证据表明，这种描述过于简单化。许多G蛋白偶联受体与一种以上的G蛋白结合，导致配体选择性激动现象，其描述了激动剂区分不同G蛋白信号传导途径的能力。已发现大量G蛋白偶联受体（包括组胺H1受体）具有混杂G蛋白偶联和配体选择性激动作用。H1受体的刺激通过Gq/11蛋白的激活导致过敏样症状，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。开发选择性激活GS-蛋白通路的药物，从而避免过敏样副作用，可能成为中枢神经系统疾病治疗的新途径。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，这是开发有前途的新的信号转导途径选择性H1受体激动剂的基础。

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.