GRKs as Key Modulators of Opioid Receptor Function

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mechanisms responsible for opioid-induced tolerance and addiction. The family of G protein receptor kinases (GRKs) play a pivotal role in such processes, mediating phosphorylation of residues at the C-tail of opioid receptors. Numerous strategies, such as phosphosite specific antibodies and mass spectrometry have allowed the detection of phosphorylated residues and the use of mutant knock-in mice have shed light on the role of GRK regulation in opioid receptor physiology. Here we review our current understanding on the role of GRKs in the actions of opioid receptors, with a particular focus on the MOR, the target of most commonly used opioid analgesics such as morphine or fentanyl

Facultative adjustment of pre-fledging mass loss by nestling swifts preparing for flight

Nestling birds often maintain nutritional reserves to ensure continual growth during interruptions in parental provisioning. However, mass-dependent flight costs require the loss of excess mass before fledging. Here we test whether individual variable mass loss prior to fledging is controlled through facultative adjustments by nestlings, or whether it reflects physiologically inflexible developmental schedules. We show that in the face of natural and experimental variation in nestling body mass and wing length, swifts always achieve very similar wing loadings (body mass per wing area) prior to fledging, presumably because this represents the optimum for flight. Experimental weights (approx. 5% body mass) temporarily attached to nestlings caused additional reductions in mass, such that final wing loadings still matched those of control siblings. Experimental reductions in nestling wing length (approx. 5% trimmed from feather tips) resulted in similar additional mass reductions, allowing wing loadings at fledging to approach control levels. We suggest that nestlings may assess their body mass relative to wing area via wing flapping and special ‘push-ups’ (on the tips of extended wings) performed in the nest. Thus, by facultatively adjusting body mass, but not wing growth, nestling swifts are always able to fledge with aerodynamically appropriate wing loadings

Chronique des tendances de la société française

[fre] La modification du partage de la valeur ajoutée dans les années soixante-dix, au profit de la part salariale, est due en partie à l'accroissement de la dépense sociale — et des prélèvements sociaux — consécutif au ralentissement de la croissance qui suivit le premier choc pétrolier. Entre 1970 et 1981, l'alourdissement de la dépense sociale — exprimé en pourcentage du PIB — est très comparable dans trois grands pays européens : la France, la RFA et le Royaume-Uni. Cependant, l'évolution du partage de la valeur ajoutée y est très différente : très forte poussée de la part salariale en France, stabilité en RFA, baisse au Royaume-Uni. Cette étude a pour objectif d'analyser dans quelle mesure les disparités existant entre ces trois pays dans le mode de financement de la protection sociale peuvent expliquer ces divergences d'évolution. En France, la part de la dépense sociale financée par la fiscalité est très faible. La charge repose à presque 80 % sur des prélèvements sociaux assis sur la rémunération des salariés. L'évaluation des contributions des salaires nets et des cotisations sociales à l'évolution des parts salariales permet de montrer que les disparités de mode de financement ont constitué un facteur évident — sans être le premier — de différenciation du partage de la valeur ajoutée. Le déterminant majeur réside dans les évolutions des parts salariales nettes de cotisations sociales. Ce sont elles, pour l'essentiel, qui expliquent les divergences entre pays. Plus précisément, la disparité d'évolution des parts salariales entre la RFA et la France est déterminée — pour les quatre cinquièmes — par l'inflexion du pouvoir d'achat des salaires nets allemands, juste après le premier choc, tandis que prévaut en France une assez forte rigidité salariale. Entre le Royaume-Uni et

Functional mapping of the N-terminal arginine cluster and C-terminal acidic residues of Kir6.2 channel fused to a G protein-coupled receptor

Ion channel-coupled receptors (ICCRs) are original man-made ligand-gated ion channels created by fusion of G protein-coupled receptors (GPCRs) to the inward-rectifier potassium channel Kir6.2. GPCR conformational changes induced by ligand binding are transduced into electrical current by the ion channel. This functional coupling is closely related to the length of the linker region formed by the GPCR C-terminus (C-ter) and Kir6.2 N-terminus (N-ter). Manipulating the GPCR C-ter length allows to finely tune the channel regulation, both in amplitude and sign (opening or closing Kir6.2). In this work, we demonstrate that the primary sequence of the channel N-terminal domain is an additional parameter for the functional coupling with GPCRs. As for all Kir channels, a cluster of basic residues is present in the N-terminal domain of Kir6.2 and is composed of 5 arginines which are proximal to the GPCR C-ter in the fusion proteins. Using a functional mapping approach, we demonstrate the role of specific arginines (R27 and R32) for the function of ICCRs, indicating that the position and not the cluster of positively-charged arginines is critical for the channel regulation by the GPCR. Following observations provided by molecular dynamics simulation, we explore the hypothesis of interaction of these arginines with acidic residues, and using site-directed mutagenesis, we identified aspartate D307 and glutamate E308 residues as critical for the function of ICCRs. These results demonstrate the critical role of the N-terminal and C-terminal charged residues of Kir6.2 for its allosteric regulation by the fused GPCR