GPCRs signal a Nobel Prize

Abstract

This special issue of Trends in Pharmacological Sciences is devoted to the study of G-protein-coupled receptors (GPCRs) in celebration of the 2012 Nobel Prize in Chemistry recently awarded to Robert Lefkowitz and Brian Kobilka for their pioneering work in the field. Both researchers are long-time esteemed contributors to TiPS, and Brian Kobilka serves on our Editorial Board. Thus, we are especially pleased to take this opportunity to congratulate them on their great science and to highlight some of the exciting ongoing developments in GPCR research. The topic is one that is clearly already of keen interest to the TiPS audience: of the top 25 most downloaded articles over the past 2 years, eight focus on GPCRs. This is a testament to the importance of these proteins in drug development and to the rapid pace at which new breakthroughs are occurring. Thirty years ago, these receptors were little more than a scientific hypothesis. Then Robert Lefkowitz, together with Kobilka and others, launched the modern study of GPCRs by first cloning and sequencing the genes for the β adrenoceptors (βARs). It took another 20 years for Kobilka's group to produce the first detailed crystal structure of the β2AR, but since then, a dozen crystal structures have followed. In this issue, Terry Kenakin provides some perspective on the Nobel award by examining how far the field of GPCR research has come in a few short years, thanks in great part to tireless efforts from Lefkowitz, Kobilka, and their colleagues.Marta Filizola and Lakshmi A. Devi kick off the reviews section with a look at how the crystal structures of the four opioid receptor subtypes provide unprecedented molecular details of opioid ligand binding and specificity. The authors argue persuasively that these structures will be important tools to guide the discovery of safer and more efficient opioid therapeutics.We then turn to histamine receptors (HxRs) with related review articles from Andrea Strasser and Roland Seifert and colleagues. First, Strasser et al. summarize the current knowledge on HxR orthologs as a case study for species-dependent activity of GPCR ligands. They highlight species-specific differences in many areas of GPCR pharmacology, including ligand-binding sites, the roles of extracellular domains in ligand binding and receptor activation, agonist-independent receptor activity, thermodynamics of ligand–receptor interaction, receptor activation mechanisms, and ligand-specific receptor conformations. Second, Seifert et al. examine current knowledge on endogenously expressed human HxRs as well as hHxRs recombinantly expressed in mammalian and insect cells. Their analysis underscores the crucial message that multiple systems and parameters must be studied across related receptors to create a complete picture of their pharmacology.Next, J. Robert Lane, Patrick M. Sexton, and Arthur Christopoulos address an important question in GPCR pharmacology: could linking of orthosteric and allosteric pharmacophores to yield ‘bitopic’ ligands be an approach to achieve improved receptor affinity or selectivity? The authors review emerging evidence and discuss the potential of bitopic ligands in GPCR drug discovery.Finally, the special issue closes with an in-depth feature review by Ed Hulme on GPCR activation. This review interprets GPCR structures through the focus provided by extensive mutagenesis studies on muscarinic receptors, revealing an activation mechanism that is both modular and dynamic. The author highlights specific motifs based around highly conserved residues that drive the functionality of the seven-transmembrane receptors.We thank all the contributors to this special issue of Trends in Pharmacological Sciences and we hope you enjoy reading it as much as we enjoyed putting it together.