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Adhesion G protein-coupled receptors (aGPCRs) are a class of structurally and functionally highly intriguing cell surface receptors with essential functions in health and disease. Thus, they display a vastly unexploited pharmacological potential. Our current understanding of the physiological functions and signaling mechanisms of aGPCRs form the basis for elucidating further molecular aspects. Combining these with novel tools and methodologies from different fields tailored for studying these unusual receptors yields a powerful potential for pushing aGPCR research from singular approaches toward building up an in-depth knowledge that will facilitate its translation to applied science. In this review, we summarize the state-of-the-art knowledge on aGPCRs in respect to structure-function relations, physiology, and clinical aspects, as well as the latest advances in the field. We highlight the upcoming most pressing topics in aGPCR research and identify strategies to tackle them. Furthermore, we discuss approaches how to promote, stimulate, and translate research on aGPCRs 'from bench to bedside' in the future.

5 HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors., Significance Statement-This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond to specific cues in their environment. However, the relationship between stimulus and response for each GPCR is difficult to predict due to diversity in natural signal transduction architecture and expression. Using genome engineering in yeast, we constructed an insulated, modular GPCR signal transduction system to study how the response to stimuli can be predictably tuned using synthetic tools. We delineated the contributions of a minimal set of key components via computational and experimental refactoring, identifying simple design principles for rationally tuning the dose response. Using five different GPCRs, we demonstrate how this enables cells and consortia to be engineered to respond to desired concentrations of peptides, metabolites, and hormones relevant to human health. This work enables rational tuning of cell sensing while providing a framework to guide reprogramming of GPCR-based signaling in other systems.

ISI Document Delivery No.: CT6ZY Times Cited: 1 Cited Reference Count: 126 Cited References: Fischer Carol L., 2014, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, V1841, P319 Legrand, Philippe Rioux, Vincent Wiley-blackwell Ark sb, 1969, gastroenterology, v56, p214; International audience; In the past 50 years, saturated fatty acids (SFAs) have played a key role in hypotheses relating diet to the risk of coronary heart disease. More recently, the international debate questioning the role of reducing intakes of saturated fat in the prevention of cardiovascular diseases has been re-opened. According to the past negative assumption, SFAs are indeed still considered as a single group even if it is now well-known that they do not have similar levels in common foods, nor similar metabolic fates and cellular functions. In addition, recent findings on the metabolism and biological functions of individual SFAs show that they have important and specific roles in the cells. Elucidated biochemical mechanisms such as SFA protein acylation (N-myristoylation, S-palmitoylation and ghrelin octanoylation) and regulation of gene transcription are presented. In terms of physiology, SFAs are involved for instance in lipogenesis, fat deposition, polyunsaturated fatty acid bioavailability and apoptosis. The variety of their functions demonstrates that SFAs should no longer be considered as a single group. Consequences on the current nutritional dietary recommendations are finally discussed. The international debate questioning the role of reducing intakes of saturated fat in the prevention of cardiovascular diseases has recently been re-opened. Saturated fatty acids are indeed still considered as a single group even if it is now well-known that they do not have similar levels in common foods, nor similar metabolic fates and cellular functions. The variety of their functions demonstrates that saturated fatty acids should no longer be considered as a single group. Consequences on the current nutritional dietary recommendations are finally discussed.

The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK(1)-R antagonists.