G Protein‐Coupled Receptors

Abstract Among membrane‐bound receptors that recognise regulatory messages (hormones, neurotransmitters, photon, odours, etc.), the seven transmembrane receptors coupled to G proteins (G protein‐coupled receptors, GPCRs) are the most numerous. They represent 3% of the total number of genes in human genome. Following activation by those messages, GPCRs activate one or several heterotrimeric G proteins (α, β and γ subunits) by stimulating the guanosine diphosphate/guanosine triphosphate (GTP) exchange on the nucleotide binding site. The GTP form of the subunits activate effectors such as enzymes (e.g. the adenylyl cyclase) or channels. GPCRs can also trigger G protein‐independent signalling. GPCRs are targets for more than 30% of the drugs used in human therapy. Progress has been made recently on the structure and activation of GPCRs, thanks to the crystallisation of more than 60 GPCRs bound to agonists, antagonists and inverse‐agonists as well as a cocrystallisation between β2‐adrenergic receptors and its associated G protein. Key Concepts: Cell–cell communication involved messages (hormone, neurotransmitter growth factors, odorant, etc.) and receptors, the majority of them being GPCRs. GPCRs are seven transmembrane receptors. They form homo‐ or heterodimers. There are three main classes of GPCRs differing in their primary sequences. The class 3 is the more original one having its binding site within an extracellular structure called ‘Venus fly trap’. During evolution, mutations have tinkered the GPCR structure in order to allow recognition of ligands as diverse as photon, odorant, sugar, proteins, etc. Virus, like human immunodeficiency virus (HIV), uses GPCRs such as those recognising chemokines (CCR5, CXCR3) to enter specialised cells such as macrophages or lymphocytes. GPCRs are allosteric molecules and drugs can be developed enhancing or silencing the effect of the natural ligand without having any effect by themselves. Mutations of GPCR are responsible of pathologies. These mutations can render the receptor constitutively active or inactive. Analysis of GPCR structures using crystallisation and nuclear magnetic resonance (NMR) indicates that many ‘active’ and ‘inactive’ conformations do exist for each GPCR. They are stabilised by chemically different agonists, inverse‐agonists or antagonists. The fully ‘active conformation’ is only obtained when the GPCR occupied by an agonist is associated with a G‐protein.