Structure, function and pharmacology of G protein-coupled receptors: State-of-the-art and future challenges

Hans Bräuner Osborne


Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

5th HTRF Symposium, Avignon, France

G protein-coupled receptors (GPCRs) constitute one of the largest gene families in the human genome and mediate signaling from a broad range of endogenous signaling molecules. About half of the approximately 720 GPCR genes code for olfactory receptors sensing smell and taste whereas 345 GPCR genes code for non-olfactory receptors. Many of the latter mediate extremely important receptor responses for neurotransmitters and hormones such as GABA, glutamate, serotonin, dopamine and adrenaline. Due to their important functions many GPCR genes have been linked to diseases and represent the largest group of drug targets. GPCRs predominantly activate intracellular G proteins upon activation. 15 G proteins have been cloned, which have been sub-divided into four classes termed Gq, Gi, Gs and G12/13, that subsequently activate/inhibit intracellular signaling pathways such as inositol phosphate or cAMP generation. In addition some receptors recruit ß-arrestin upon activation which lead to internalization and ERK phosphorylation independently of a G protein. Each receptor couples to a limited set of these signaling pathways and thereby elicit specific cellular effects. Approximately 130 non-olfactory GPCRs remains classified as orphans meaning that they have not been linked with endogenous signaling molecules. Each deorphanization (i.e. pairing receptor and endogenous ligand) holds the potential to unravel completely novel signaling molecules and physiological mechanisms. Thus previous deorphanizations have completely redefined our understanding of human physiological mechanisms providing important basic knowledge as well as laid the foundation for understanding disease mechanisms and development of novel drugs. The last few years have brought a number of technological breakthroughs which have led to increased understanding of GPCRs such as illucidation of the 3D structures of inactive and active receptor conformations, computer-based drug design, biased agonism, nutrient sensing by promiscuous GPCRs, and deorphanizations. In the present talk, state-of-the-art and future directions within these concepts will be discussed.

GPCR research from A to Z , Kinases, Phosphorylated proteins