ATP as a presynaptic modulator

© 2000 Elsevier Science Inc.There is considerable evidence that ATP acts as a fast transmitter or co-transmitter in autonomic and sensory nerves mostly through activation of ionotropic P2X receptors but also through metabotropic P2Y receptors. By analogy, the observations that ATP is released from stimulated central nervous system (CNS) nerve terminals and that responses to exogenously added ATP can be recorded in central neurons, lead to the proposal that ATP might also be a fast transmitter in the CNS. However, in spite of the robust expression of P2 receptor mRNA and binding to P2 receptors in the CNS, the demonstration of central purinergic transmission has mostly remained elusive. We now review evidence to suggest that ATP may also act presynaptically rather than solely postsynaptically in the nervous system.Fundação Ciência e Tecnologia and European nio

Inhibition by ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases into adenosine and channeling to adenosine A1 receptors

© 1998 Society for NeuroscienceATP analogs substituted in the γ-phosphorus (ATPγS, β, γ-imido-ATP, and β, γ-methylene-ATP) were used to probe the involvement of P2 receptors in the modulation of synaptic transmission in the hippocampus, because their extracellular catabolism was virtually not detected in CA1 slices. ATP and γ-substituted analogs were equipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC50 of 17–22 μM). The inhibitory effect of ATP and γ-phosphorus-substituted ATP analogs (30 μM) was not modified by the P2 receptor antagonist suramin (100 μM), was inhibited by 42–49% by the ecto-5’- nucleotidase inhibitor and α, β-methylene ADP (100 μM), was inhibited by 74–85% by 2 U/ml adenosine deaminase (which converts adenosine into its inactive metabolite-inosine), and was nearly prevented by the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 nM). Stronger support for the involvement of extracellular adenosine formation as a main requirement for the inhibitory effect of ATP and γ-substituted ATP analogs was the observation that an inhibitor of adenosine uptake, dipyridamole (20 μM), potentiated by 92–124% the inhibitory effect of ATP and γ-substituted ATP analogs (10 μM), a potentiation similar to that obtained for 10 μM adenosine (113%). Thus, the present results indicate that inhibition by extracellular ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ectonucleotidases and channeling of the generated adenosine to adenosine A1 receptors.This work was supported by Junta Nacional de Investigação Cientifica e Tecnológica, Praxis XXI, Gulbenkian Foundation, and European Union (BIOMED 2 programme

ATP is released from nerve terminals and from activated muscle fibres on stimulation of the rat phrenic nerve

Nerve stimulation increases the concentration of ATP in the synaptic cleft, which can act as a neurotransmitter or as a presynaptic neuromodulator. Using the luciferin-luciferase assay, we observed that the extracellular concentration of ATP increased by 11-26 nM over a basal concentration of 6 nM, in a frequency dependent manner (1-5 Hz), in the adult rat phrenic nerve-hemidiaphragm preparation. This ATP release depends on nerve activity since it was abolished by tetrodotoxin (1 [mu]M) and is strictly dependent on the presence of extracellular calcium. However, more than half of this nerve-evoked release of ATP is derived from activated muscle fibres since the selective post-synaptic nicotinic receptor antagonist, [alpha]-bungarotoxin (1 [mu]M), inhibited by over 60% the evoked release of ATP. The presently observed post-synaptic release of ATP together with the previously reported lack of post-synaptic effects of ATP and to the ability of ATP to act as a presynaptic modulator open the possibility that ATP may behave as a retrograde messenger at this neuromuscular junction.http://www.sciencedirect.com/science/article/B6T0G-47S6YPN-X/1/e09fe63a6ed4383fc2ed5996ece6ac4

HPC Cloud for Scientific and Business Applications: Taxonomy, Vision, and Research Challenges

High Performance Computing (HPC) clouds are becoming an alternative to on-premise clusters for executing scientific applications and business analytics services. Most research efforts in HPC cloud aim to understand the cost-benefit of moving resource-intensive applications from on-premise environments to public cloud platforms. Industry trends show hybrid environments are the natural path to get the best of the on-premise and cloud resources---steady (and sensitive) workloads can run on on-premise resources and peak demand can leverage remote resources in a pay-as-you-go manner. Nevertheless, there are plenty of questions to be answered in HPC cloud, which range from how to extract the best performance of an unknown underlying platform to what services are essential to make its usage easier. Moreover, the discussion on the right pricing and contractual models to fit small and large users is relevant for the sustainability of HPC clouds. This paper brings a survey and taxonomy of efforts in HPC cloud and a vision on what we believe is ahead of us, including a set of research challenges that, once tackled, can help advance businesses and scientific discoveries. This becomes particularly relevant due to the fast increasing wave of new HPC applications coming from big data and artificial intelligence.Comment: 29 pages, 5 figures, Published in ACM Computing Surveys (CSUR

G protein-coupled receptor 37 (GPR37) emerges as an important modulator of adenosinergic transmission in the striatum

G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein-coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive Parkinson's disease promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death (Takahashi and Imai, 2003). Interestingly, we have demonstrated previously that GPR37 heteromerizes with adenosine A2A receptor (A2AR) in the striatum (Morató et al., 2017; Sokolina et al., 2017). In addition, we also reported some functional consequences of this direct interaction, whereby GPR37 deletion enhanced striatal A2AR cell surface expression with a concomitant increase in A2AR agonist-mediated cAMP accumulation (Morató et al., 2017); accordingly, an enhancement of A2AR agonist-induced catalepsy and antagonist-induced locomotor activity was observed upon GPR37 deletion (Morató et al., 2017). Overall, it has been hypothesized that GPR37 might hold a chaperone-like activity controlling A2AR cell surface targeting and function. However, the precise physiological function of GPR37 still is unidentified. The current findings now provide additional evidence for the role of GPR37 as a repressor of A2AR function

Caffeine, adenosine receptors, and synaptic plasticity

Copyright ©2012 IOS Press All rights reserved.Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) for 3 weeks, displayed a concentration of caffeine of circa 22 μM in the hippocampus. It is known that selective adenosine A1 receptor antagonists facilitate, whereas selective adenosine A2A receptor antagonists attenuate, long term potentiation (LTP) in the hippocampus. Although caffeine is a non-selective antagonist of adenosine receptors, it attenuates frequency-induced LTP in hippocampal slices in a manner similar to selective adenosine A2A receptor antagonists. These effects of low micromolar concentration of caffeine (30 μM) are maintained in aged animals, which is important when a possible beneficial effect for caffeine in age-related cognitive decline is proposed. Future studies will still be required to confirm and detail the involvement of A1 and A2A receptors in the effects of caffeine on hippocampal synaptic plasticity, using both pharmacological and genetic approaches.The work was supported by Fundação para a Ciência e Tecnologia and Fundação Oriente

Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease

Objective: Machado–Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington’s disease, we now tested their ability to control MJD-associated neurodegeneration. Methods: MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis. Results: Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2A R inactivation (knockout). Interpretation: Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD

CHARACTERIZATION AND ANTIFUNGAL ACTIVITY OF THE ESSENTIAL OIL OF TAGETES MINUTA FRONT OF THE CRYPTOCOCCUS SPP. ISOLATES FROM THE ENVIRONMENT

Objective: This study evaluated the chemical composition and antifungal activity of the essential oil of inflorescences of Tagetes minuta (EOTM) belonging to the Asteraceae family against Cryptococcus spp. This microorganism is the encapsulated yeast-like and is recognized as an opportunistic fungal pathogen of great clinical importance.Methods: The inflorescences of T. minuta were collected in Itaara/RS, Brazil, in April 2013, and identification of the components was performed by GC-MS. The species of fungi are environmental isolates of Cryptococcus spp. identified by direct examination with India ink, urease test, culture and agar Niger medium canavanine glycine bromothymol blue, and all fungi isolates were confirmed by the use of automated panel MicroScan® Rapid Yeast ID (SIEMENS®). ATCC strains of C. gattii, C. neoformans and C. grubii belonging to the Microbiology Laboratory of the Centro Universitário Franciscano of Santa Maria/RS, Brazil were also used. The antifungal activity of the EOTM was evaluated by microdilution.Results: Most strains of Cryptococcus spp. were sensitive to EOTM even at low concentrations, except when the microorganism in question was Cryptococcus grubii which the essential oil showed a weak antifungal action.Conclusion: The EOTM appears as promising in prospecting for new drugs for the treatment of cryptococcosis.Keywords: Cryptococcosis, Natural products, Antifungal, Marigol

Overexpression of Adenosine A2A receptors in rats: effects on depression, locomotion, and anxiety

Copyright: © 2014 Coelho, Alves, Canas, Valadas, Shmidt, Batalha, Ferreira, Ribeiro, Bader, Cunha, do Couto and Lopes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Adenosine A2A receptors (A2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer's disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer's disease.Joana E. Coelho, Vânia L. Batalha and Diana G. Ferreira were supported by a grant from Fundação para a Ciência e Tecnologia (FCT); Paula M. Canas and Rodrigo A. Cunha were supported by FCT (PTDC/SAU-NSC/122254/2010) and Defense Advanced Research Projects Agency (DARPA, grant 09-68-ESR- FP-010). Luísa V. Lopes is an Investigator FCT, funded by Fundação para a Ciência e Tecnologia (PTDC-099853/2009) and Bial.info:eu-repo/semantics/publishedVersio

The effects of different concentrations of the α2-Adrenoceptor Agonist Medetomidine on basal excitatory synaptic transmission and synaptic plasticity in hippocampal slices of adult mice

α2-Adrenoceptor agonists are used frequently in human and veterinary anesthesia as sedative/analgesic drugs. However, they can impair cognition. Little is known about the concentration-dependent effects of α2-adrenoceptor agonists on synaptic plasticity, the neurophysiological basis of learning and memory. Therefore, we investigated the effects of different concentrations of medetomidine, an α2-adrenoceptor agonist, on basal excitatory synaptic transmission and on 2 forms of synaptic plasticity: paired-pulse facilitation (PPF) and long-term potentiation (LTP).Funding: This work was supported by FCT (Lisbon, Portugal) and cofunded by COMPETE: 01-0124-FEDER-009497 (Lisbon, Portugal), through the project grants PTDC/CVT/099022/2008 and PTDC/SAU-NSC/122254/2010 and through a personal PhD grant (SFRH /BD/48883/2008) to Patrícia do Céu Oliveira Ribeiro and by QREN (09-68-ESR-FP-010).info:eu-repo/semantics/publishedVersio