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

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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.