title: Pilot the pulse: controlling the multiplicity of receptor dynamics.
abstract: G protein-coupled receptors (GPCRs) are involved in almost every (patho)physiological process, which explains their importance as drug targets. GPCRs have long been regarded as on/off-switches, which is reflected by direct activation or blockade of these receptors through the majority of marketed GPCR drugs. In recent years, however, our view of GPCRs has changed dramatically. GPCRs are now appreciated as integrative and highly dynamic signaling machines which can adopt numerous distinct conformations enabling them to initiate a highly ramified signaling network. We argue here that it may be possible to chemically encode distinct signaling profiles into ligands by rational ligand design. We exemplify our hypothesis by fine-tuning partial and biased agonism, thereby exploiting two new principles of GPCR modulation - dynamic and dualsteric ligand binding. We propose that the emerging understanding of the multiplicity of receptor dynamics will eventually lead to rationally designed new drugs which pilot the pulse; in other words, that stabilize distinct receptor states to fine-tune GPCR signaling.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. Electronic address: andreas.bock@uni-wuerzburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bock
authors.affiliation: Molecular-, Cellular-, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Strasse 3, 53121 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Strasse 3, 53121 Bonn, Germany. Electronic address: k.mohr@uni-bonn.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: G protein-coupled receptors; biased agonism; dualsteric binding; dynamic ligand binding; partial agonism; rational ligand design