GPCRs exhibit a common architecture of seven transmembrane helices (TMs) linked by intracellular loops and extracellular loops (ECLs). Given their peripheral location to the site of G-protein interaction, it might be assumed that ECL segments merely link the important TMs within the helical bundle of the receptor. However, compelling evidence has emerged in recent years revealing a critical role for ECLs in many fundamental aspects of GPCR function, which supported by recent GPCR crystal structures has provided mechanistic insights. This review will present current understanding of the key roles of ECLs in ligand binding, activation and regulation of both family A and family B GPCRs. LINKED ARTICLESThis article is part of a themed section on the Molecular Pharmacology of G Protein-Coupled Receptors (GPCRs). To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-6. To view the 2010 themed section on the same topic visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2010.159.issue-5/issuetoc Abbreviations A2AR, A2A adenosine receptor; AT1R, angiotensin II type 1 receptor; b1AR, b1-adrenergic receptor; b2AR, b2-adrenergic receptor; C5aR, complement factor 5a receptor; CAM, constitutively activating mutation; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; CRF, corticotropin-releasing factor; D3R (D2R), D3 (D2) dopamine receptor; GLP-1, glucagon-like peptide-1; ECL, extracellular loop; H1R, histamine H1 receptor; HIV-1, human immunodeficiency virus type 1; M2R (M4R), M2 (M4) muscarinic acetylcholine receptor; NDI, nephrogenic diabetes insipidus; PACAP, pituitary adenylyl cyclase-activating peptide; PTH, parathyroid hormone; TM, transmembrane helix; V1aR, V1a vasopressin receptor; V2R, V2 vasopressin receptor IntroductionGPCRs form the largest class of membrane proteins in the human genome, with >800 unique receptors. They are central to cell signalling and are of great commercial value to the pharmaceutical industry worldwide, with~50% of clinically marketed drugs and~25% of top-selling drugs targeting this receptor family (Lagerström and Schiöth, 2008). GPCRs are activated by a wide variety of agonists which differ with respect to chemical class, physical properties and size -from photons and small biogenic amines to peptides and large glycoproteins (Hill, 2006).Historically, it was envisaged that binding any agonist induced the 'on' conformation that activated a single G-protein type to initiate an intracellular signal. It is now recognized that GPCR signalling is much more complex than this. Individual GPCRs can activate multiple types of G-protein, not just one type, and signalling can be G-protein independent, such as b-arrestin-dependent GPCR activation of MAPK (Azzi et al., 2003). Furthermore, there is compelling evidence to indicate that the classification of an individual ligand can be dictated by the signalling system being observed. For example, the peptide ligand SP-G is an antagonist for V 1a vasopressin receptor (V1aR) inositol phos...

Objective: To compare non-responders and responders to a dietary survey with respect to demographic variables and intention to choose selected breakfast foods, and to examine if there was any systematic change in number of food items reported during a 7 d recording period. Design: Cross-sectional survey. Setting: Mo Èlndal, Sweden. Subjects: All pupils in 5th, 7th and 9th grades in the municipality were asked to complete a questionnaire during school hours. All those present (n 1584, 92% of total) answered questions about lifestyle factors and about intentions, attitudes and beliefs concerning high-®bre bread and milk with varying fat content. All subjects in the initial sample were asked to ®ll in a 7 d record of food consumed. Acceptable food records were completed by 69% of the initial participants. Results: Subjects not completing the food record differed signi®cantly from participants with respect to demographic, lifestyle and dietary factors. Dropout was more common among those who reported not usually eating breakfast and among those intending to drink whole milk for breakfast. A decline in reported food items during the recording period was also observed. Conclusions: Two sources of bias were observed here, one indicating signi®cant differences between nonparticipants and participants, the other suggesting the presence of a time-dependent trend in number of recorded foods. It is likely such biases are present in other dietary surveys involving schoolchildren, and should be taken into consideration in the design, analysis and interpretation of such studies. Sponsorship: The Swedish Council for Forestry and Agricultural Research and the National Institute for Public Health.