Gravin orchestrates protein kinase A and 2-adrenergic receptor signaling critical for synaptic plasticity and memory

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage

Phosphorylation of PDE4A5 by MAPKAPK2 attenuates fibrin degradation via p75 signalling

Phosphodiesterases (PDEs) shape local cAMP gradients to underpin the specificity of receptor function. Key to this process is the highly defined nature of the intra-cellular location of PDEs in the cell. PDE4A5 is a PDE isoform that specifically degrades cAMP and is known to associate with the p75 neurotrophin receptor (p75NTR) where it modulates cAMP signalling cascades that regulate extracellular matrix remodelling in the lungs. Here we map and validate novel protein–protein interaction sites that are important for formation of the PDE4A5–p75NTR complex and show, for the first time, that phosphorylation of PDE4A5 by MAPKAPK2 enhances PDE4A5 interaction with p75NTR and that this, in turn, serves to attenuate fibrin degradation

Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability

YesEffective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3- interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic AMP. Together, these findings reveal a new functionally important mechanism linking SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via interaction with and stabilisation of cavin-1.This work was supported by project grants to T.M.P. from the Chief Scientist Office (ETM/226), British Heart Foundation (PG12/1/ 29276, PG 14/32/30812), and a National Health Service Greater Glasgow and Clyde Research Endowment Fund (2011REFCH08). P.F.P. was supported by the National Institutes of Health grant DK097708. J.J.L.W. was supported by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). N.A. was supported by a Saudi Government PhD Scholarship. This work was also supported in part by equipment grants to T.M.P. from Diabetes UK (BDA 11/0004309) and Alzheimer’s Research UK (ARUK-EG2016A-3)

Hypoxia modulates platelet purinergic signalling pathways.

BACKGROUND:  Hypoxia resulting from ascent to high-altitude or pathological states at sea level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP pathways, research into the impact of hypoxia on platelet ADP pathways is highly important. METHODS:  Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700 m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor, respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay. RESULTS:  Hypobaric hypoxia significantly reduced the ability of a fixed concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP phosphorylation. However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide-6 amide. CONCLUSION:  Our results provide evidence of increased P2Y1 receptor activity at high altitude and suggest down-regulation of the P2Y12 pathway through increased VASP phosphorylation. These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea level patients prescribed platelet inhibitors and warrant further investigation

Critical Behavior of the Ferromagnetic Ising Model on a Sierpinski Carpet: Monte Carlo Renormalization Group Study

We perform a Monte Carlo Renormalization Group analysis of the critical behavior of the ferromagnetic Ising model on a Sierpi\'nski fractal with Hausdorff dimension $d_f\simeq 1.8928$. This method is shown to be relevant to the calculation of the critical temperature $T_c$ and the magnetic eigen-exponent $y_h$ on such structures. On the other hand, scaling corrections hinder the calculation of the temperature eigen-exponent $y_t$. At last, the results are shown to be consistent with a finite size scaling analysis.Comment: 16 pages, 7 figure

Monte Carlo Renormalization Group Analysis of Lattice ϕ4\phi^4 Model in D=3,4D=3,4

We present a simple, sophisticated method to capture renormalization group flow in Monte Carlo simulation, which provides important information of critical phenomena. We applied the method to $D=3,4$ lattice $\phi^4$ model and obtained renormalization flow diagram which well reproduces theoretically predicted behavior of continuum $\phi^4$ model. We also show that the method can be easily applied to much more complicated models, such as frustrated spin models.Comment: 13 pages, revtex, 7 figures. v1:Submitted to PRE. v2:considerably reduced redundancy of presentation. v3:final version to appear in Phys.Rev.

Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

Background:There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples.Methods:About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample.Results:We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC).Conclusions:We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression

New results from the NA57 experiment

We report results from the experiment NA57 at CERN SPS on hyperon production at midrapidity in Pb-Pb collisions at 158 $A$ GeV/$c$ and 40 $A$ GeV/$c$. $\Lambda$, $\Xi$ and $\Omega$ yields are compared with those from the STAR experiment at the higher energy of the BNL RHIC. $\Lambda$, $\Xi$, $\Omega$\ and preliminary $K_S^0$ transverse mass spectra are presented and interpreted within the framework of a hydro-dynamical blast wave model.Comment: 8 pages, 3 figures, contribution to the proceedings of The XXXVIIIth Rencontres de Moriond "QCD and High Energy Hadronic Interactions

Expansion dynamics of Pb-Pb collisions at 40 A GeV/c viewed by negatively charged hadrons

In this paper we present results on transverse mass spectra and Hanbury-Brown and Twiss correlation functions of negatively charged hadrons, which are expected to be mostly negative pions, measured in Pb-Pb collisions at 40 A GeV/c beam momentum. Based on these data, the collision dynamics and the space-time extent of the system at the thermal freeze-out are studied over a centrality range corresponding to the most central 53% of the Pb--Pb inelastic cross section. Comparisons with freeze-out conditions of strange particles and HBT results from other experiments are discussed.Comment: 29 pages, 18 figure

Results on hyperon production from the NA57 experiment

Recent results on hyperon production in Pb--Pb collisions from the NA57 experiment are reported. Strangeness enhancement and the transverse mass spectra properties at 158 GeV per nucleon are described.Comment: submitted to Acta Phys. Hung. A (Heavy Ion Physics