Molecular pharmacology of G protein‐coupled receptors

Abstract

The joint meeting provided a broader focus on GPCRs. In particular, this themed issue has been focused on the challenges involved in translating basic science into therapeutically useful approaches. The GPCRs included in these articles by authoritative researchers are largely used to illustrate particular paradigms or approaches to drug discovery but include a variety of orphan receptors, protease-activated receptors PAR1 and PAR4, adenosine A 1 and A 3 receptors, mGlu 5 receptors, muscarinic M 1 and M 2 receptors and adrenoceptors.In the symposium examining GPCR targets in cardiovascular disease, Nicola Smith and colleagues (Ngo et al., 2016) examine approaches that show promise for identifying tools to study orphan receptors. Many orphan GPCRs display interesting phenotypes in models such as knockout mice that suggest that they could be useful therapeutic targets. However, in many cases, progress in developing agonist or antagonist tools for these receptors is hindered by a lack of knowledge of the cognate ligand or of compounds that modulate activity. Traditional approaches such as reverse pharmacology, that involves high throughput screening against the orphan receptor expressed in a heterologous system, have been successful in some instances, but deorphanization tends to be slow (about once a year) and is getting slower as the remaining orphan GPCRs fall into the difficult category. There is also an increasing realization that some orphan GPCRs may not have a cognate ligand and rely on constitutive activity or the formation of heterodimers for activity. However and increasingly, the use of in silico structure-based approaches provides another avenue to the discovery of orphan GPCR modulators. A critical feature of this approach is the increasing number of GPCR X-ray structures (33 to date) that has allowed the development of virtual ligand screening (VLS) with the goal of identifying ligands interacting with orphan GPCRs. The authors identify the main problem with this approach -that deorphanization usually requires knowledge of ligands that interact with the receptor -and suggest solutions. This involves identification of the G proteins and signalling pathways activated by the receptor followed by a screen to identify active compounds. These are then used to develop a VLS model with multiple iterations to improve the library and model with the eventual development of novel ligands. Although there are relatively few examples at the moment, the article illustrates how VLS has been used to gain information on the binding of putative ligands to orphan receptors and to develop a pathway from a cognate ligand to a compound with therapeutic potential. Justin Hamilton and Shauna French (French and Hamilton, 2016) examine the emerging role of PAR4, a relatively little known PAR, in disease. They describe the interesting phenotypes associated with PAR4 knockout mice, protection against thrombosis with a mild bleeding phenotype, reduced inflammation and

Calcium-Sensing Receptor Mediates β-Amyloid-Induced Synaptic Formation Impairment and Cognitive Deficits via Regulation of Cytosolic Phospholipase A2/Prostaglandin E2 Metabolic Pathway

“…Aβ has been shown to interact directly with CaSR via a proximity ligation assay (Diez-Fraile et al, 2013 ; Leach et al, 2015 ). CaSR, a member of the G protein-coupled receptor (GPCRs) C family, is a seven-transmembrane protein (Brauner-Osborne et al, 2007 ; Conigrave and Ward, 2013 ; Summers, 2016 ). CaSR has been detected in the hippocampus which is an important brain structure that is essential for spatial memory, language learning, and episodic memory (Ferry et al, 2000 ).…”