The Year In G Protein-Coupled Receptor Research

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2010-01, Vol.24 (1), p.261-274
• Main Authors: Millar, Robert P, Newton, Claire L
• Format: Article
• Language: English
• Subjects: Animals; Biomedical Research; Congresses as Topic; Drug Discovery; Endocrinology - trends; Gene Expression Regulation; Humans; Ligands; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - classification; Receptors, G-Protein-Coupled - physiology; Signal Transduction
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2009-0473

I (R.P.M.) presented “The Year In G Protein-Coupled Receptor Research” at ENDO 2009. I first described the diversity of ligands and the five families into which the approximately 800 G protein-coupled receptors (GPCRs) are grouped, their basic structural architectures, their preeminent role in signaling, and the enormous scope for developing drugs targeted at GPCRs. I then spoke about some of the exciting breakthroughs in solving the atomic level structures of the active state of rhodopsin, β2-adrenergic, β1-adrenergic, and A2A-adenosine receptors. I also described studies on the structural changes accompanying the activation of the rhodopsin family of GPCRs. From these recent technical advances, we can anticipate that many more GPCR structures will emerge, which will afford us greater insight into their common and unique structural features and, particularly, the mechanisms underlying their activation. These insights will guide us in our understanding of how GPCRs operate, both in the normal and pathological situation. Although these crystal structures are highly informative, it is important to recognize that they represent static frozen conformations of a single GPCR state. New biophysical techniques are therefore being utilized to facilitate the dynamic monitoring of GPCR structural changes in relation to ligand activation. Solving of the crystal structures of GPCRs has also presented the real possibility of using the information of the ligand-binding pocket to allow in silico screening for novel small-molecule ligands. I then reviewed the concept of ligand-induced selective signaling of GPCRs, which is opening up new insights into more selective drug development. The assembly of GPCRs as homo- and heterooligomers and their phosphorylation and association with a vast array of trafficking and signal-modulating proteins are emerging as major mechanisms underlying the functioning of GPCRs. Differential expression and recruitment of these proteins provide a mechanism for subtle physiological regulation of cellular activity. Finally, I mentioned some of the GPCRs that have lately come to the fore as novel regulators in endocrinology. These included fatty acid-specific GPCRs expressed in pancreatic β-cells and novel neuroendocrine GPCRs regulating reproduction.