Editorial

No abstract available

George Baillie on peptide array, a technique that transformed research on phosphodiesterases

George Baillie speaks to Francesca Lake (Managing Editor, Future Science OA). George Baillie is a Professor and PI within the Institute of Cardiovascular and Medical Sciences at the University of Glasgow (Glasgow, UK). His research over the last 15 years has examined many aspects of the cAMP signaling pathway in disease and he has published over 140 papers on the subject. His major discovery was that phosphodiesterases are ‘compartmentalized’, and it is their location within cells that direct their function. The Baillie/Houslay laboratory was the first to discover a specific function for a single isoform of PDE4 (namely PDE4D5 with β-arrestin desensitizes the β2-adrenergic receptor). His laboratory has since gone on to ascribe functions to several other PDE4 isoforms. He is a founder and director of Sannox Therapeutics, a spin-out venture within University of Glasgow. He is also a member of the Editorial Board of Future Science OA and Co-Editor of Cellular Signalling

Heat Shock Protein 20 (HSP20) is a novel substrate for Protein Kinase D1 (PKD1)

Heat shock protein 20 (HSP20) has cardioprotective qualities, which are triggered by PKA phosphorylation. PKD1 is also a binding partner for HSP20, and this prompted us to investigate whether the chaperone was a substrate for PKD1. We delineate the PKD1 binding sites on HSP20 and show for the first time HSP20 is a substrate for PKD1. Phosphorylation of HSP20 by PKD1 is diminished by pharmacological or siRNA reduction of PKD1 activity and is enhanced following PKD1 activation. Our results suggest that both PKA and PKD1 can both phosphorylate HSP20 on serine 16 but that PKA is the most dominant

Testing for Neglected Nonlinearity in Long Memory Models

This paper constructs tests for the presence of nonlinearity of unknown form in addition to a fractionally integrated, long memory component in a time series process. The tests are based on artificial neural network structures and do not restrict the parametric form of the nonlinearity. The tests only require a consistent estimate of the long memory parameter. Some theoretical results for the new tests are obtained and detailed simulation evidence is also presented on the power of the tests. The new methodology is then applied to a wide variety of economic and financial time series.Long memory, Non-linearity, Artificial neural networks, Realized volatility, Absolute returns, Real exchange rates, Unemployment

Nonlinear Models with Strongly Dependent Processes and Applications to Forward Premia and Real Exchange Rates

This paper considers estimation and inference in some general non linear time series models which are embedded in a strongly dependent, long memory process. Some new results are provided on the properties of a time domain MLE for these models. The paper also includes a detailed simulation study which compares the time domain MLE with a two step estimator, where the Local Whittle estimator has been initially employed to filter out the long memory component. The time domain MLE is found to be generally superior to two step estimation. Further, the simulation study documents the difficulty of precisely estimating the parameter associated with the speed of transition. Finally, the fractionally integrated, nonlinear autoregressive- ESTAR model is found to be extremely useful in representing some financial time series such as the forward premium and real exchange rates.Non-linearity, ESTAR models, Strong dependence, Forward premium, Real exchange rates

Editorial: frontiers in the pharmacological manipulation of intracellular cAMP levels

No abstract available

Non-genetic therapeutic approaches to Canavan disease

Canavan disease (CD) is a rare leukodystrophy characterized by diffuse spongiform white matter degeneration, dysmyelination and intramyelinic oedema with consequent impairment of psychomotor development and early death. The molecular cause of CD has been identified as being mutations of the gene encoding the enzyme aspartoacylase (ASPA) leading to its functional deficiency. The physiological role of ASPA is to hydrolyse N-acetyl-l-aspartic acid (NAA), producing l-aspartic acid and acetate; as a result, its deficiency leads to abnormally high central nervous system NAA levels. The aim of this article is to review what is currently known regarding the aetiopathogenesis and treatment of CD, with emphasis on the non-genetic therapeutic strategies, both at an experimental and a clinical level, by highlighting: (a) major related hypotheses, (b) the results of the available experimental simulatory approaches, as well as (c) the relevance of the so far examined markers of CD neuropathology. The potential and the limitations of the current non-genetic neuroprotective approaches to the treatment of CD are particularly discussed in the current article, in a context that could be used to direct future experimental and (eventually) clinical work in the field

The role and therapeutic targeting of α-, β- and γ-secretase in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly and its prevalence is set to increase rapidly in coming decades. However, there are as yet no available drugs that can halt or even stabilize disease progression. One of the main pathological features of AD is the presence in the brain of senile plaques mainly composed of aggregated β amyloid (Aβ), a derivative of the longer amyloid precursor protein (APP). The amyloid hypothesis proposes that the accumulation of Aβ within neural tissue is the initial event that triggers the disease. Here we review research efforts that have attempted to inhibit the generation of the Aβ peptide through modulation of the activity of the proteolytic secretases that act on APP and discuss whether this is a viable therapeutic strategy for treating AD.<p></p> Alzheimer's disease (AD) is the most common form of dementia in the elderly but as yet there are no drugs that can halt the progression of this disease. In a theory called the ‘amyloid hypothesis’, researchers have proposed that the accumulation of a small protein fragment called beta amyloid or Aβ within brain tissue is the event which triggers Alzheimer's disease. Aβ is a derivative of the longer amyloid precursor protein (APP). Here we review research efforts that have attempted to inhibit the generation of Aβ through modulation of proteins called secretases which cut APP into Aβ. Author edits made on: 20 May 2015

Phosphorylation of ezrin on Thr567 is required for the synergistic activation of cell spreading by EPAC1 and protein kinase A in HEK293T cells

Recent studies have demonstrated that the actin binding protein, ezrin, and the cAMP-sensor, EPAC1, cooperate to induce cell spreading in response to elevations in intracellular cAMP. To investigate the mechanisms underlying these effects we generated a model of EPAC1-dependent cell spreading based on the stable transfection of EPAC1 into HEK293T (HEK293T–EPAC1) cells. We found that direct activation of EPAC1 with the EPAC-selective analogue, 8-pCPT-2′-O-Me-cAMP (007), promoted cell spreading in these cells. In addition, co-activation of EPAC1 and PKA, with a combination of the adenylate cyclase activator, forskolin, and the cAMP phosphodiesterase inhibitor, rolipram, was found to synergistically enhance cell spreading, in association with cortical actin bundling and mobilisation of ezrin to the plasma membrane. PKA activation was also associated with phosphorylation of ezrin on Thr567, as detected by an electrophoretic band mobility shift during SDS-PAGE. Inhibition of PKA activity blocked ezrin phosphorylation and reduced the cell spreading response to cAMP elevation to levels induced by EPAC1-activation alone. Transfection of HEK293T–EPAC1 cells with inhibitory ezrin mutants lacking the key PKA phosphorylation site, ezrin-Thr567Ala, or the ability to associate with actin, ezrin-Arg579Ala, promoted cell arborisation and blocked the ability of EPAC1 and PKA to further promote cell spreading. The PKA phospho-mimetic mutants of ezrin, ezrin-Thr567Asp had no effect on EPAC1-driven cell spreading. Our results indicate that association of ezrin with the actin cytoskeleton and phosphorylation on Thr567 are required, but not sufficient, for PKA and EPAC1 to synergistically promote cell spreading following elevations in intracellular cAMP

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42 mediated cytotoxicity

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4,5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4,5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the co-localisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1-42 cytotoxicity in our cell model