A5027701585- Phosphodiesterase function and regulation
- Receptor Mechanisms and Signaling
- Cholinesterase and Neurodegenerative Diseases
- Renin-Angiotensin System Studies
- Protein Kinase Regulation and GTPase Signaling
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- Alzheimer's disease research and treatments
- Signaling Pathways in Disease
- Neuroscience and Neuropharmacology Research
- Ubiquitin and proteasome pathways
- Chemical synthesis and alkaloids
- Synthesis and Catalytic Reactions
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Ion Transport and Channel Regulation
- Antifungal resistance and susceptibility
- Cell Adhesion Molecules Research
- Cellular transport and secretion
- Pulmonary Hypertension Research and Treatments
- Bacterial biofilms and quorum sensing
- Heat shock proteins research
- Nitric Oxide and Endothelin Effects
- Cardiomyopathy and Myosin Studies
- Endoplasmic Reticulum Stress and Disease
University of Glasgow
2016-2025
University of Dundee
2017
Glasgow Life
2016
Veneto Institute of Molecular Medicine
2008-2015
University of Oslo
2015
Oslo University Hospital
2015
Institutt for Eksperimentell Medisinsk Forskning
2015
University of Oxford
2015
University of Utah
2015
Oslo Nye Høyskole
2015
The disrupted in schizophrenia 1 ( DISC1 ) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role the disorder unknown. Here we report that encoding phosphodiesterase 4B PDE4B by balanced translocation subject diagnosed with and relative chronic psychiatric illness. PDEs inactivate adenosine 3′,5′-monophosphate (cAMP), second messenger implicated learning, memory, mood. We show interacts UCR2 domain of elevation cellular cAMP leads to dissociation from an...
Catecholamines signal through the beta2-adrenergic receptor by promoting production of second messenger adenosine 3',5'-monophosphate (cAMP). The magnitude this is restricted desensitization receptors their binding to beta-arrestins and cAMP degradation phosphodiesterase (PDE) enzymes. We show that coordinate both processes recruiting PDEs activated in plasma membrane mammalian cells. In doing so, limit activation membrane-associated cAMP-activated protein kinase simultaneously slowing rate...
Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity been proposed a substrate storage. Here, we examine the impact brief deprivation on dendritic structure. In mice, find that five hours decreases spine numbers selectively hippocampal area CA1 and increased activity filamentous actin severing protein cofilin. Recovery normalizes these structural alterations. Suppression cofilin function prevents loss,...
Extracellular polymeric material (EP), comprising the matrix of Candida albicans biofilms, was isolated and its composition compared with that EP obtained from culture supernatants planktonically grown (suspended) organisms. Both preparations consisted carbohydrate, protein, phosphorus hexosamine, but biofilm contained significantly less total carbohydrate (41%) protein (5%) than planktonic EP. It also had a higher proportion glucose (16%) galactose, suggesting it might possess components...
Phosphorylation of the β 2 adrenoreceptor (β AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory (G s ) to inhibitory i ). β-Arrestins recruit cAMP-degrading PDE4 phosphodiesterases AR, thus controlling PKA activity at membrane. Here we investigate a role for recruitment in regulating G switching AR. In human embryonic kidney 293 cells overexpressing recombinant stimulation with isoprenaline recruits β-arrestins 1 and...
A simple catheter disk model system was used to study the development in vitro of mixed species biofilms Candida albicans and Staphylococcus epidermidis, two organisms commonly found catheter-associated infections. Two strains S. epidermidis were used: a slime-producing wild type (strain RP62A) slime-negative mutant M7). In fungal-bacterial biofilms, both staphylococcal showed extensive interactions with C. albicans. The susceptibility 48-h fluconazole, vancomycin mixtures drugs determined...
Summary Two model biofilm systems, involving growth on disks of catheter material or cylindrical cellulose filters, were used to investigate the structure Candida albicans biofilms. To assess importance dimorphism in development, biofilms produced by two wild-type strains compared with those formed morphological mutants, incapable yeast and hyphal growth, respectively. Scanning electron microscopy thin sections examined light revealed that consisted distinct layers: a thin, basal layer...
Challenge of COS1 cells with the adenylyl cyclase activator forskolin led to activation recombinant PDE4A8, PDE4B1, PDE4C2 and PDE4D5 cAMP‐specific phosphodiesterase long isoforms. Forskolin challenge did not activate mutant PDE4 isoforms where serine target residue (STR) within protein kinase A (PKA) consensus phosphorylation site in Upstream Conserved Region 1 (UCR1) was mutated alanine. The PKA inhibitor, H89, ablated wild‐type Activated caused vitro isoforms, but those STR An antiserum...
The cAMP-specific phosphodiesterase family 4, subfamily D, isoform 3 (PDE4D3) is shown to have FQF and KIM docking sites for extracellular signal-regulated kinase 2 (ERK2) (p42<sup>MAPK</sup>). These straddle the target residue, Ser<sup>579</sup>, ERK2 phosphorylation of PDE4D3. Mutation either or both these prevented from being co-immunoprecipitated with PDE4D3, ablated ability epidermal growth factor inhibit PDE4D3 through action in transfected COS cells, attenuated phosphorylate...
ABSTRACT A perfused biofilm fermentor, which allows growth-rate control of adherent microbial populations, was used to assess whether the susceptibility Candida albicans biofilms antifungal agents is dependent on growth rate. Biofilms were generated under conditions glucose limitation and with drugs at a high concentration (20 times MIC). Amphotericin B produced greater reduction in number daughter cells eluates than ketoconazole, fluconazole, or flucytosine. Similar decreases cell counts...
Protein kinase A (PKA) is a key regulatory enzyme that, on activation by cAMP, modulates wide variety of cellular functions. PKA isoforms type I and II possess different structural features biochemical characteristics, resulting in nonredundant function. However, how expressed the same cell manage to perform distinct functions soluble intracellular messenger, remains be established. Here, we provide mechanism for function subsets cardiac myocytes demonstrate that PKA-RI PKA-RII, binding...
PDE4B and PDE4D provide >90% of PDE4 cAMP phosphodiesterase activity in human embryonic kidney (HEK293B2) cells. Their selective small interference RNA (siRNA)-mediated knockdown potentiates isoprenaline-stimulated protein kinase A (PKA) activation. Whereas endogenous co-immunoprecipitates with βarrestin, does not, even upon knockdown. Ectopic overexpression PDE4B2 confers co-immunoprecipitation βarrestin. Knockdown PDE4D, but not PDE4B, amplifies phosphorylation the β2-adrenergic receptor...
There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling pathway organized to form transduction units function deliver specific messages. Such organization results in local activation of PKA subsets through generation confined intracellular gradients cAMP, but mechanisms responsible for limiting diffusion cAMP largely remain be clarified. In this study, by performing real-time imaging we show prostaglandin 1 stimulation generates...
Cerebral cavernous malformations (CCMs) are alterations in brain capillary architecture that can result neurological deficits, seizures, or stroke. We recently demonstrated CCM3, a protein mutated familial CCMs, resides predominantly within the STRIPAK complex (striatin interacting phosphatase and kinase). Along with contains Ser/Thr PP2A. The PP2A holoenzyme consists of core catalytic subunit along variable scaffolding regulatory subunits. Within STRIPAK, striatin family members act as also...
The cardiac I(Ks) potassium channel is a macromolecular complex consisting of alpha-(KCNQ1) and beta-subunits (KCNE1) the A kinase-anchoring protein (AKAP) Yotiao (AKAP-9), which recruits kinase A) phosphatase 1 to channel. Here, we have tested hypothesis that specific cAMP phosphodiesterase (PDE) isoforms PDE4D family are expressed in heart also part signaling contribute its regulation by cAMP. co-immunoprecipitated with channels hearts mice expressing In myocytes isolated from these mice,...
Bayesian inference–based modeling identifies the most likely paths through a signaling network.
Rationale : Chronic elevation of 3′-5′-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and hypertrophy. However, enhancement particular aspects cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger ability generate multiple functional outcomes in response different extracellular stimuli strict fidelity, feature that relies on spatial segregation pathway components microdomains. Objective...