Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion

GRK2; AKT; Ischemia-reperfusionGRK2; AKT; Isquemia-reperfusiónGRK2; AKT; Isquèmia-reperfusióBackground: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term in patients and in experimental models of heart failure. However, whether GRK2 levels change at early time points following myocardial I/R and its functional impact during this period remain to be established. Methods: We have investigated the temporal changes of GRK2 expression and their potential relationships with the cardioprotective AKT pathway in isolated rat hearts and porcine preclinical models of I/R. Findings: Contrary to the maladaptive up-regulation of GRK2 reported at later times after myocardial infarction, successive GRK2 phosphorylation at specific sites during ischemia and early reperfusion elicits GRK2 degradation by the proteasome and calpains, respectively, thus keeping GRK2 levels low during early I/R in rat hearts. Concurrently, I/R promotes decay of the prolyl-isomerase Pin1, a positive regulator of AKT stability, and a marked loss of total AKT protein, resulting in an overall decreased activity of this pro-survival pathway. A similar pattern of concomitant down-modulation of GRK2/AKT/Pin1 protein levels in early I/R was observed in pig hearts. Calpain and proteasome inhibition prevents GRK2/Pin1/AKT degradation, restores bulk AKT pathway activity and attenuates myocardial I/R injury in isolated rat hearts. Interpretation: Preventing transient degradation of GRK2 and AKT during early I/R might improve the potential of endogenous cardioprotection mechanisms and of conditioning strategies.Our laboratories are supported by Instituto de Salud Carlos III, Spain (grant PI-16/00232; RETICS-RIC-RD12/0042/0021 to DGD, co-funded with European Regional Development Fund-FEDER contribution, and grants PI14-00435 and PI17-00576 to PP), by Ministerio de Economía; Industria y Competitividad (MINECO) of Spain (grant SAF2017-84125-R to F.M.); by CIBERCV-Instituto de Salud Carlos III, Spain (grant CB16/11/00479 to DGD and CB16/11/00278 to F.M, co-funded with European Regional Development Fund-FEDER contribution), and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to F.M. We also acknowledge institutional support to the CBMSO from Fundación Ramón Areces. This work is dedicated to the memory of our colleague and friend Dr. David García-Dorado, who sadly passed away during the final revision stage of this manuscript

The role of ACKR3 in breast, lung, and brain cancer

Recent reports regarding the significance of chemokine receptors in disease have put a spotlight on atypical chemokine receptor 3 (ACKR3). This atypical chemokine receptor is overexpressed in numerous cancer types and has been involved in the modulation of tumor cell proliferation and migration, tumor angiogenesis, or resistance to drugs, thus contributing to cancer progression and metastasis occurrence. Here, we focus on the clinical significance and potential mechanisms underlying the pathologic role of ACKR3 in breast, lung, and brain cancer and discuss its possible relevance as a prognostic factor and potential therapeutic target in these contexts.European Union H2020-MSCA Program [Grant Agreement 64183], ONCORNET to P.M., M.J.S., and F.M.; Ministerio de Economía, Industria y Competitividad of Spain [Grant SAF2017-84125-R] to F.M.; CIBERCV-Instituto de Salud Carlos III, Spain [Grant CB16/11/00278] to F.M.; cofunded with European FEDER contribution, Comunidad de Madrid [B2017/BMD-3671-INFLAMUNE] to F.M.; Fundación Ramón Areces to F.M.; Portuguese Foundation for Science and Technology [Grant SFRH/BD/136574/2018] to M.N.; Netherlands Organization for Scientific Research NWO: Vici [Grant 016.140.657] to M.J.S.; and grants from CNRS, INSERM, Université de Montpellier and Fondation pour la Recherche Médical

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo

© The Author(s).[Background]: Insulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). However, whether GRK2 affects insulin secretion or if GRK2 can control incretin actions in vivo remains to be analyzed. [Results]: Using GRK2 hemizygous mice, isolated pancreatic islets, and model β-cell lines, we have uncovered a relevant physiological role for GRK2 as a regulator of incretin-mediated insulin secretion in vivo. Feeding, oral glucose gavage, or administration of GLP-1R agonists in animals with reduced GRK2 levels (GRK2+/− mice) resulted in enhanced early phase insulin release without affecting late phase secretion. In contrast, intraperitoneal glucose-induced insulin release was not affected. This effect was recapitulated in isolated islets and correlated with the increased size or priming efficacy of the readily releasable pool (RRP) of insulin granules that was observed in GRK2+/− mice. Using nanoBRET in β-cell lines, we found that stimulation of GLP-1R promoted GRK2 association to this receptor and that GRK2 protein and kinase activity were required for subsequent β-arrestin recruitment. [Conclusions]: Overall, our data suggest that GRK2 is an important negative modulator of GLP-1R-mediated insulin secretion and that GRK2-interfering strategies may favor β-cell insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications.We acknowledge support by Ministerio de Economía y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and BFU2017-89336-R to MV); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., co-funded with European FEDER contribution); CIBER de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), Instituto de Salud Carlos III (CB07/08/0029 to MV); and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM; Medical Research Council to AT and BJ

A Spectroscopic Orbit for Regulus

We present a radial velocity study of the rapidly rotating B-star Regulus that indicates the star is a single-lined spectroscopic binary. The orbital period (40.11 d) and probable semimajor axis (0.35 AU) are large enough that the system is not interacting at present. However, the mass function suggests that the secondary has a low mass (M_2 > 0.30 M_sun), and we argue that the companion may be a white dwarf. Such a star would be the remnant of a former mass donor that was the source of the large spin angular momentum of Regulus itself.Comment: 18 pages, 2 figures, ApJL in pres

G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases

G protein-coupled receptor kinase 2 (GRK2) is a central signaling node involved in the modulation of many G protein-coupled receptors (GPCRs) and also displaying regulatory functions in other cell signaling routes. GRK2 levels and activity have been reported to be enhanced in patients or in preclinical models of several relevant pathological situations, such as heart failure, cardiac hypertrophy, hypertension, obesity and insulin resistance conditions, or non-alcoholic fatty liver disease (NAFLD), and to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Therefore, targeting GRK2 by different strategies emerges as a potentially relevant approach to treat cardiovascular disease, obesity, type 2 diabetes, or NAFLD, pathological conditions which are frequently interconnected and present as co-morbidities

The interplay between double exchange, super-exchange, and Lifshitz localization in doped manganites

Considering the disorder caused in manganites by the substitution of Mn by Fe or Ga, we accomplish a systematic study of doped manganites begun in previous papers. To this end, a disordered model is formulated and solved using the Variational Mean Field technique. The subtle interplay between double exchange, super-exchange, and disorder causes similar effects on the dependence of T_C on the percentage of Mn substitution in the cases considered. Yet, in La$_{2/3}$Ca$_{1/3}$Mn$_{1-y}$Ga$_y$O$_3$ our results suggest a quantum critical point (QCP) for $y\approx 0.1-0.2$, associated to the localization of the electronic states of the conduction band. In the case of La$_x$Ca$_x$Mn$_{1-y}$Fe$_y$O$_3$ (with $x=1/3,3/8$) no such QCP is expected.Comment: 6 pages + 3 postscript figures. Largely extended discussio

On the origin of the Boson peak in globular proteins

We study the Boson Peak phenomenology experimentally observed in globular proteins by means of elastic network models. These models are suitable for an analytic treatment in the framework of Euclidean Random Matrix theory, whose predictions can be numerically tested on real proteins structures. We find that the emergence of the Boson Peak is strictly related to an intrinsic mechanical instability of the protein, in close similarity to what is thought to happen in glasses. The biological implications of this conclusion are also discussed by focusing on a representative case study.Comment: Proceedings of the X International Workshop on Disordered Systems, Molveno (2006

CFHT Adaptive Optics Observations of the Central Kinematics in M15

We have used an Imaging Fabry-Perot Spectrophotometer with the Adaptive Optics Bonnette on the Canada-France-Hawaii Telescope to measure stellar radial velocities in the globular cluster M15. An average seeing of 0.15" full-width at half maximum, with the best-seeing image having 0.09", allowed us to measure accurately the velocities for five stars within 1" of the center of M15. Our estimate of the second moment of the velocity distribution inside a radius of 2" is 11.5 km/s, the same value we find out to a radius of about 6". However, the projected net rotation does increase dramatically at small radii, as our previous observations led us to suspect. The rotation amplitude inside a radius of 3.4" is v = 10.4 +- 2.7 km/s and the dispersion after removing the rotation is sigma = 10.3 +- 1.4 km/s, so v/sigma = 1 in this region. In addition, the position angle (PA) of the projected rotation axis differs by 100 degrees from that of the net cluster rotation at larger radii. Current theoretical models do not predict either this large an increase in the rotation amplitude or such a change in the PA. However, a central mass concentration, such as a black hole, could possibly sustain such a configuration. The rotation increase is consistent with the existence of a central dark mass concentration equal to 2500 M_solar.Comment: 23 pages, emulateapj style, accepted for publication in The Astronomical Journal, Marc