Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin

Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homologue neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins. The association between spinophilin and PP1 is increased in the striatum of animal models of Parkinson's disease (PD). However, mechanisms that regulate the association of spinophilin and neurabin with PP1 are unclear. Here, we report that the association between spinophilin and PP1α or PP1γ1 was increased by CDK5 expression and activation in a heterologous cell system. This increased association is at least partially due to phosphorylation of PP1. Conversely, CDK5 expression and activation decreased the association of PP1 with neurabin. As with dopamine depletion, methamphetamine (METH) abuse causes persistent alterations in dopamine signaling which influence striatal medium spiny neuron function and biochemistry. Moreover, both METH toxicity and dopamine depletion are associated with deficits in motor control and motor learning. Pathologically, we observed a decreased association of spinophilin with PP1 in rat striatum evaluated one month following a binge METH paradigm. Behaviorally, we found that loss of spinophilin recapitulates rotarod pathology previously observed in dopamine-depleted and METH-treated animals. Together, these data have implications in multiple disease states associated with altered dopamine signaling such as PD and psychostimulant drug abuse and delineate a novel mechanism by which PP1 interactions with spinophilin and neurabin may be differentially regulated

Does spinophilin play a role in alteration of NMDAR phosphorylation?

poster abstractNormal brain function requires proper organization of downstream signaling pathways. This organization can be modulated by protein phosphorylation. Protein phosphorylation is a balance of phosphatases, such as protein phosphatase 1 (PP1), and kinases such as protein kinase A (PKA) and cyclin dependent kinase 5 (CDK5). Proper targeting of these proteins is critical for their normal function and is perturbed in various disease states. Spinophilin is critical in targeting PP1 to various substrates making it important in regulating the phosphorylation state and thus the function of various proteins including glutamate receptors, such as AMPARs and NMDARs. NMDARs are abundant postsynaptic proteins that are critical for normal synaptic communication. It has been reported that NMDAR phosphorylation modulates channel function. Here we aim to understand if spinophilin regulates NMDAR phosphorylation and function as well as the mechanisms by which the spinophilin NMDAR interaction are altered. Specifically, we have found that the presence of spinophilin decreases the abundance of PP1 bound to NMDAR. This affect was not observed when a PP1 binding-deficient spinophilin mutant (F451A) was expressed. Furthermore, activation of endogenous PKA and/or overexpression of PKA catalytic subunit robustly increased the association between spinophilin and GluN1 and C-terminal tail of the GluN2B subunit of the NMDAR. Conversely, these associations are decreased when CDK5 is present. Our future studies will evaluate the role of spinophilin in regulating the phosphorylation state of the NMDAR. Taken together, our data demonstrate that spinophilin can associate with multiple subunits of the NMDAR in HEK293 cells and that protein kinases can biphasically modulate these associations

Adolescent Perceptions of Injury and Pressures of Returning to Sport: A Retrospective Qualitative Analysis

The increase in sport participation among adolescents has led to the rise in sport-related injuries, many of which have unique characteristics based on the patient, their perceptions, and the pressures faced when returning to sport. The purpose of this study was to identify the underlying factors that contributed to adolescents’ perceptions of injury and the various pressures they experienced when returning to sport. Two themes emerged from the study: support and fear. Support was provided to participants through development, care, and the environment. Fear was the factor that affected the participant in their return to sport, which came in the form of worry and doubt

The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5

Spinophilin is the most abundant protein phosphatase 1 targeting protein in the postsynaptic density of dendritic spines. Spinophilin associates with myriad synaptic proteins to regulate normal synaptic communication; however, the full complement of spinophilin interacting proteins and mechanisms regulating spinophilin interactions are unclear. Here we validate an association between spinophilin and the scaffolding protein, disks large-associated protein 3 (SAP90/PSD-95 associated protein 3; SAPAP3). Loss of SAPAP3 leads to obsessive-compulsive disorder (OCD)-like behaviors due to alterations in metabotropic glutamate receptor (mGluR) signaling. Here we report that spinophilin associates with SAPAP3 in the brain and in a heterologous cell system. Moreover, we have found that expression or activation of group I mGluRs along with activation of the mGluR-dependent kinase, protein kinase C β, enhances this interaction. Functionally, global loss of spinophilin attenuates amphetamine-induced hyperlocomotion, a striatal behavior associated with dopamine dysregulation and OCD. Together, these data delineate a novel link between mGluR signaling, spinophilin, and SAPAP3 in striatal pathophysiology

EMPRESS : A European project to enhance process control through improved temperature measurement

A new European project called EMPRESS, funded by the EURAMET program ‘European Metrology Program for Innovation and Research,’ is described. The 3 year project, which started in the summer of 2015, is intended to substantially augment the efficiency of high-value manufacturing processes by improving temperature measurement techniques at the point of use. The project consortium has 18 partners and 5 external collaborators, from the metrology sector, high-value manufacturing, sensor manufacturing, and academia. Accurate control of temperature is key to ensuring process efficiency and product consistency and is often not achieved to the level required for modern processes. Enhanced efficiency of processes may take several forms including reduced product rejection/waste; improved energy efficiency; increased intervals between sensor recalibration/maintenance; and increased sensor reliability, i.e., reduced amount of operator intervention. Traceability of temperature measurements to the International Temperature Scale of 1990 (ITS-90) is a critical factor in establishing low measurement uncertainty and reproducible, consistent process control. Introducing such traceability in situ (i.e., within the industrial process) is a theme running through this project

Direct extreme UV-lithographic conversion of metal xanthates into nanostructured metal sulfide layers for hybrid photovoltaics

We present a versatile strategy toward the preparation of nanostructured metal sulfide layers, which exploits the photosensitivity of metal xanthates as a powerful tool for lithographic structuring. Using extreme ultraviolet interference lithography (EUV-IL), we successfully realized well-defined column and comb nanostructures. This approach provides new pathways to fabricate highly ordered structured metal sulfide layers with periodicities far below 100 nm for potential application in hybrid solar cells. © 2013 The Royal Society of Chemistry

Two-vibron bound states in alpha-helix proteins : the interplay between the intramolecular anharmonicity and the strong vibron-phonon coupling

The influence of the intramolecular anharmonicity and the strong vibron-phonon coupling on the two-vibron dynamics in an $\alpha$-helix protein is studied within a modified Davydov model. The intramolecular anharmonicity of each amide-I vibration is considered and the vibron dynamics is described according to the small polaron approach. A unitary transformation is performed to remove the intramolecular anharmonicity and a modified Lang-Firsov transformation is applied to renormalize the vibron-phonon interaction. Then, a mean field procedure is realized to obtain the dressed anharmonic vibron Hamiltonian. It is shown that the anharmonicity modifies the vibron-phonon interaction which results in an enhancement of the dressing effect. In addition, both the anharmonicity and the dressing favor the occurrence of two different bound states which the properties strongly depend on the interplay between the anharmonicity and the dressing. Such a dependence was summarized in a phase diagram which characterizes the number and the nature of the bound states as a function of the relevant parameters of the problem. For a significant anharmonicity, the low frequency bound states describe two vibrons trapped onto the same amide-I vibration whereas the high frequency bound states refer to the trapping of the two vibrons onto nearest neighbor amide-I vibrations.Comment: may 2003 submitted to Phys. Rev.

Tuning the conductivity along atomic chains by selective chemisorption

Adsorption of Au on vicinal Si(111) surfaces results in growth of long-range ordered metallic quantum wires. In this paper, we utilized site-specific and selective adsorption of oxygen to modify chemically the transport via different channels in the systems Si(553)-Au and Si(557)-Au. They were analyzed by electron diffraction and four-tip STM-based transport experiments. Modeling of the adsorption process by density functional theory shows that the adatoms and rest atoms on Si(557)-Au provide energetically favored adsorption sites, which predominantly alter the transport along the wire direction. Since this structural motif is missing on Si(553)-Au, the transport channels remain almost unaffected by oxidation. © 2017 American Physical Society.DFG/FOR/170

Unravelling cationic cellulose nanofibril hydrogel structure: NMR spectroscopy and small angle neutron scattering analyses

Stiff, elastic, viscous shear thinning aqueous gels are formed upon dispersion of low weight percent concentrations of cationically modified cellulose nanofibrils (CCNF) in water. CCNF hydrogels produced from cellulose modified with glycidyltrimethylammonium chloride, with degree of substitution (DS) in the range 10.6(3)–23.0(9)%, were characterised using NMR spectroscopy, rheology and small angle neutron scattering (SANS) to probe the fundamental form and dimensions of the CCNF and to reveal interfibrillar interactions leading to gelation. As DS increased CCNF became more rigid as evidenced by longer Kuhn lengths, 18–30 nm, derived from fitting of SANS data to an elliptical cross-section, cylinder model. Furthermore, apparent changes in CCNF cross-section dimensions suggested an “unravelling” of initially twisted fibrils into more flattened ribbon-like forms. Increases in elastic modulus (7.9–62.5 Pa) were detected with increased DS and 1H solution-state NMR T1 relaxation times of the introduced surface –N+(CH3)3 groups were found to be longer in hydrogels with lower DS, reflecting the greater flexibility of the low DS CCNF. This is the first time that such correlation between DS and fibrillar form and stiffness has been reported for these potentially useful rheology modifiers derived from renewable cellulose