GPCR dimerization, a handbook

Abstract

The G Protein-Coupled Receptor Handbook represents a collection of articles on current topics in the field of G protein-coupled receptors (GPCR). As noted in the forward to the book, the GPCR family of receptors is the largest class of membrane bound receptors, is functionally very diverse and is the hottest target of pharmaceuticals today. As a result, the task of capturing even a small slice of current advances in the field is daunting. Similarly, it is difficult to assemble such a collection of articles and to keep pace with the rapid progress inherently associated with such a large and diverse family of receptors. The most up-to-date chapters of the book, based on references in the literature, capture the state of the GPCR field at the beginning of 2004.The handbook is organized into four sections. The first section covers four different aspects of GPCR structure and function: structure–function relationships; conformational changes upon receptor activation; folding and maturation; and trafficking. Despite the high-resolution crystal structures that have been reported on the dark (inactive) state of rhodopsin since the pioneering work of Palczewski and colleagues in 2000 [1xCrystal structure of rhodopsin: a G protein-coupled receptor. Palczewski, K. et al. Science. 2000; 289: 739–745Crossref | PubMed | Scopus (4495)See all References][1], there is still no comprehensive model for how any single GPCR is activated, and much less is known concerning the structure of GPCR dimers or oligomers. Nevertheless, the chapters devoted to structure and mechanism provide a valuable overview of the mutational and biophysical studies used to derive many of the receptor structure–activity correlations described in the literature.The second section of the handbook reports on proteins that interact with GPCRs. Each chapter in this section describes a different set of proteins and together they most closely approach the concept of a handbook. The first four chapters discuss heterotrimeric G-proteins, RGS (regulator of G-protein signaling) proteins, GPCR kinases and the arrestin family of proteins. A final chapter provides a short general review of methods that have been used to identify GPCR-interacting proteins and different interaction domains, and how these proteins serve to modulate GPCR signaling.The third section is the largest and covers many different aspects of the functional role of GPCR dimerization. The chapters in this section offer an excellent overview of the emergence of GPCR dimers and higher order oligomers as a concept in the field. However, the lag in publication of the Handbook misses important challenges to the view that the GPCR dimer is the functional form of the receptor [2xMonomeric G-protein-coupled receptor as a functional unit. Chabre, M. and le Maire, M. Biochemistry. 2005; 44: 9395–9403Crossref | PubMed | Scopus (163)See all References][2], as well as exciting new results that reveal crosstalk between receptors upon ligand binding [3xCrosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Guo, W. et al. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 17495–17500Crossref | PubMed | Scopus (214)See all References][3].The final section on ‘recent developments in drug discovery’ is the least comprehensive of the four sections. Only one of the three chapters, describing the potential of orphan receptors as drug targets, is focused on drug discovery.As a broad overview, The G Protein-Coupled Receptor Handbook provides an excellent resource to introduce the reader to many of the diverse areas and questions that drive research in the GPCR field. For GPCR researchers, the Handbook will probably be of most value to those with a particular interest in background studies on receptor dimerization.