G protein‐coupled receptor pharmacology—The next generation

G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome. They are widely expressed and activated by a broad range of ligands including neurotransmitters, hormones, metabolites and ions as well as sensory signals.1, 2 Accordingly, it is not surprising that GPCRs are involved in a very broad variety of physiological functions and are the largest class of drug targets being targeted by 34% of Food and Drug Administration (FDA) approved drugs.3 To enlighten and discuss the most recent developments within GPCR pharmacology, we organized a 3-day conference entitled GPCR pharmacology—The next generation at the Royal Danish Academy of Sciences and Letters in October/November 2018. To facilitate discussions and networking, the participant number was kept to just 90 people including 24 speakers and 39 poster presenters and spread among as many institutions and countries as possible, and was thus highly international with participants from 17 different countries. The conference was generously supported by Basic & Clinical Pharmacology & Toxicology and the Carlsberg Foundation. The present special issue highlights some of the interesting results and concepts which were presented and discussed at the conference. An important topic at the conference was understudied GPCRs. About 1/3 of the 400 non-olfactory GPCRs encoded in the human genome remain orphan receptors for which the endogenous ligand(s) have not yet been firmly established.4 The orphan receptors are largely unexplored and thus constitute a potential treasure trove of new knowledge about human physiology and future drug development.3 Examples include the GPR1395 and apelin6 receptors for which (potential) endogenous and surrogate ligands have been identified in recent years. The ligands, along with, for example, genetically modified mice, have been instrumental in uncovering pharmacology, physiology and therapeutic potential of these receptors. The adhesion and frizzled/smoothened GPCRs are likewise understudied, but great strides have been made in recent years with publication of, for example, new ligands, 3D structures and mechanism-of-action studies. The new developments are elegantly reviewed in the publications of the Langenhan7 and Schulte8 groups in the present special issue. Well-studied GPCRs like the dopamine and muscarinic acetylcholine receptors remain extremely important drug targets. The Javitch group have written a very interesting MiniReview describing the use and substantiating the strength of the model organism Drosophila melanogaster to study dopamine receptors and dopamine neurotransmission. Indeed, from this model system a lot of important lessons have been learned also impacting human brain function.9 Another interesting MiniReview from the Kellendonk group reviews the latest data on the highly relevant topic of how the dopamine D2 receptor modulates motivated behaviour through regulation of neuronal activity in the striatal indirect pathway.10 Finally, the Clemmensen group has taken an exciting new look at muscarinic acetylcholine receptors and written a MiniReview about their role in energy homoeostasis.11 They outline that the receptors both play a direct role in energy homoeostasis via canonical brain circuits regulating appetite and indirect roles via neurocircuits regulating motivated behaviours and emotional stress. Muscarinic acetylcholine receptors might thus be novel drug targets for treatment of obesity and type 2 diabetes.11 In recent years, allosteric modulators and biased ligands of GPCRs have become hot topics in GPCR pharmacology as the concepts hold the promise of developing ligands with fewer side effects due to, for example, higher receptor subtype or signalling pathway selectivity.12, 13 The concept of allosteric modulation was covered by several talks and posters as exemplified in the current issue by the discovery of monellin as the first naturally derived proteinaceous allosteric mGlu5 receptor agonist.14 In order to study biased signalling, it is important to cover all potential signalling pathways activated by GPCRs of which the G12/13 pathway has been understudied due to lack of efficient and pathway-specific downstream assays. This limitation has recently been resolved by the introduction of BRET/FRET assays directly monitoring G protein activation, which allow pharmacological profiling of all G protein subtypes. In this issue, the Martemyanov group describes such a novel assay for the Gα12 protein,15 which nicely complements their previously published Gα13 protein assay16 to cover both G protein subtypes of this understudied signalling pathway. Another important aspect of GPCR function is receptor desensitization and internalization. These aspects are covered by two articles from the Rosenkilde and Madsen groups. The former provides a detailed characterization of a common E354Q genetic variant of the GIP receptor, which provides a potential mechanism for the long-term functional impairment of the GIP receptor system in carriers of this variant.17 This is relevant not only as a naturally occurring receptor variant with phenotypic alterations, but also due to the long-term desensitization of the GIP system in patients with type 2 diabetes mellitus, where hyperglycaemia and enhanced levels of the endogenous agonist GIP seem to play a role.18 In the other study, the Madsen group provide a tour-de-force characterization of constitutive internalization, constitutive activity and agonist-induced internalization of more than 30 therapeutically targeted GPCRs, which, for example, reveal that Gq-coupled receptors interestingly display higher rates of constitutive internalization than Gs- and Gi-coupled receptors.19 Finally, the Bettler group has written an authoritative MiniReview of how protein-protein interactions between the GABAB receptor and a range of scaffolding/signalling proteins leads to generation of complexes regulating subcellular receptor localization, signalling kinetics and signalling pathways.20 This underlines the complexity of GPCR function, which goes far beyond the receptors themselves. This special issue demonstrates the great strides we have taken in recent years to further our knowledge about GPCR function, pharmacology and physiology. However, it also underlines how much there still is to be discovered by the next generation of GPCR pharmacologists!