G Protein-Coupled Receptors

Abstract

G protein-coupled receptors (GPCRs) mediate a wide variety of physiological processes, are clearly associated with a diverse number of human diseases, and are well-validated ‘druggable’ drug discovery targets. The molecular pharmacology of GPCRs continues to become increasingly more complex as we apply new means to study them. For example, the common occurrence of a multiplicity of G protein coupling and activation of multiple signaling pathways, the formation of multiple ligand-activated conformations and agonist trafficking, the natural occurrence of ligand- and G protein-independent signaling of GPCRs, and the potential pharmacological significance of GPCR dimerization and heterodimerization have all made GPCR drug discovery more challenging. All of these new paradigms may have an impact on successful GPCR drug discovery programs and need to be considered when developing GPCR functional screens and secondary assays. Furthermore, postgenomic evaluations indicate that there are over 100 GPCRs for which the endogenous ligand and the physiological and theraputic relevance are unknown. Target validation of this large number of potential therapeutic targets is a major focus of the pharmaceutical industry and ensures that GPCRs will continue to be one of the most important and expanding classes of drug discovery targets.