Anatomical Profiling of G Protein-Coupled Receptor Expression

SummaryG protein-coupled receptors (GPCRs) comprise the largest family of transmembrane signaling molecules and regulate a host of physiological and disease processes. To better understand the functions of GPCRs in vivo, we quantified transcript levels of 353 nonodorant GPCRs in 41 adult mouse tissues. Cluster analysis placed many GPCRs into anticipated anatomical and functional groups and predicted previously unidentified roles for less-studied receptors. From one such prediction, we showed that the Gpr91 ligand succinate can regulate lipolysis in white adipose tissue, suggesting that signaling by this citric acid cycle intermediate may regulate energy homeostasis. We also showed that pairwise analysis of GPCR expression across tissues may help predict drug side effects. This resource will aid studies to understand GPCR function in vivo and may assist in the identification of therapeutic targets

Evidence of active shortening along the eastern border of the San Rafael basement block: Characterization of the seismic source of the Villa Atuel earthquake (1929), Mendoza province, Argentina

ACLInternational audienceOn the 30 May 1929, a massive earthquake occurred in the San Rafael area (southern Mendoza province) leading to the destruction of the Villa Atuel and Las Malvinas towns. The region affected by the ground shaking covers a large part of southern South America. Although no surface breaks have been detected on the surface, several authors have pointed out active faults that could be related to the event of 1929. Using satellite imagery and field observations, we investigated two active faults situated on the eastern border of the San Rafael Block (SRB) close to or within the epicentral area. The most prominent faults are the c. 40 km long Las Malvinas and c. 30 km long Cerro Negro reverse faults which are located near the epicentral area. Geological and morphological observations allow us to describe late Pleistocene activity and estimate the long-term slip rates of these faults. Possible ruptures that match our observations and which are compatible with the cartographic length of these faults would account for a seismic moment magnitude of M0 = 2.8×1019 N m and a moment magnitude of MW = 6.9. The morphological signatures of these fault segments and the occurrence of the San Rafael earthquake suggests that the southern Mendoza Province is still currently submitted to shortening. © 2016 Cambridge University Press

Geomorphology of the Northern Great Caucasus : investigating depth geometries from surface data

ACTInternational audienc

Active deformation of the northern front of the Eastern Great Caucasus

ACTInternational audienc

Late Pleistocene tectonic activity of the eastern border of the San Rafaël block (Neuquén Basin, Argentina)

ACTInternational audienc

Late Pleistocene tectonic activity of the eastern border of the San Rafaël block (Neuquén Basin, Argentina)

ACTInternational audienc

Late Pleistocene tectonic activity of the eastern border of the San Rafaël block (Neuquén Basin, Argentina)

ACTInternational audienc

Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice

International audienceMaintenance of vascular integrity is critical for homeostasis, and temporally and spatially regulated vascular leak is a central feature of inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources of the S1P that provide this activity in vivo and its importance in modulating different inflammatory responses are unknown. We report here that mutant mice engineered to selectively lack S1P in plasma displayed increased vascular leak and impaired survival after anaphylaxis, administration of plate-let-activating factor (PAF) or histamine, and exposure to related inflammatory challenges. Increased leak was associated with increased interendothelial cell gaps in venules and was reversed by transfusion with wild-type erythrocytes (which restored plasma S1P levels) and by acute treatment with an agonist for the S1P receptor 1 (S1pr1). S1pr1 agonist did not protect wild-type mice from PAF-induced leak, consistent with plasma S1P levels being sufficient for S1pr1 activation in wild-type mice. However, an agonist for another endothelial cell G i-coupled receptor, Par2, did protect wild-type mice from PAF-induced vascular leak, and systemic treatment with pertussis toxin prevented rescue by Par2 agonist and sensitized wild-type mice to leak-inducing stimuli in a manner that resembled the loss of plasma S1P. Our results suggest that the blood communicates with blood vessels via plasma S1P to maintain vascular integrity and regulate vascular leak. This pathway prevents lethal responses to leak-inducing mediators in mouse models

Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

The in vivo roles of the hundreds of mammalian G protein–coupled receptors (GPCRs) are incompletely understood. To explore these roles, we generated mice expressing the S1 subunit of pertussis toxin, a known inhibitor of Gi/o signaling, under the control of the ROSA26 locus in a Cre recombinase–dependent manner (ROSA26PTX). Crossing ROSA26PTX mice to mice expressing Cre in pancreatic β cells produced offspring with constitutive hyperinsulinemia, increased insulin secretion in response to glucose, and resistance to diet-induced hyperglycemia. This phenotype underscored the known importance of Gi/o and hence of GPCRs for regulating insulin secretion. Accordingly, we quantified mRNA for each of the approximately 373 nonodorant GPCRs in mouse to identify receptors highly expressed in islets and examined the role of several. We report that 3-iodothyronamine, a thyroid hormone metabolite, could negatively and positively regulate insulin secretion via the Gi-coupled α2A-adrenergic receptor and the Gs-coupled receptor Taar1, respectively, and protease-activated receptor–2 could negatively regulate insulin secretion and may contribute to physiological regulation of glucose metabolism. The ROSA26PTX system used in this study represents a new genetic tool to achieve tissue-specific signaling pathway modulation in vivo that can be applied to investigate the role of Gi/o-coupled GPCRs in multiple cell types and processes