scholarly journals Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 604
Author(s):  
Zsolt Szabó ◽  
Márton Péter ◽  
László Héja ◽  
Julianna Kardos
Keyword(s):  
Epileptiform Activity ◽  
Tonic Inhibition ◽  
Fine Tuning ◽  
Network Activity ◽  
Polyamine Metabolism ◽  
Copper Uptake ◽  
Gaba Transporter ◽  
Copper Transporter ◽  
Divalent Metal Transporter ◽  
Gap Junction Channel

Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na+ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca2+ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu+/Cu2+) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu+/Cu2+ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO3 (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu+/Cu2+) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl2 (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl2 (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse.

scholarly journals Characterization of the Copper Transporters from Lotus spp. and Their Involvement under Flooding Conditions

2019 ◽  
Vol 20 (13) ◽  
pp. 3136 ◽  
Author(s):  
Francisco J. Escaray ◽  
Cristian J. Antonelli ◽  
Guillermo J. Copello ◽  
Sergi Puig ◽  
Lola Peñarrubia ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Higher Plants ◽  
Economic Losses ◽  
Copper Uptake ◽  
Copper Transporter ◽  
Copper Transporters ◽  
Transporter Family ◽  
Adaptive Mechanisms ◽  
High Prevalence ◽  
Natural Grassland

Forage legumes are an important livestock nutritional resource, which includes essential metals, such as copper. Particularly, the high prevalence of hypocuprosis causes important economic losses to Argentinian cattle agrosystems. Copper deficiency in cattle is partially due to its low content in forage produced by natural grassland, and is exacerbated by flooding conditions. Previous results indicated that incorporation of Lotus spp. into natural grassland increases forage nutritional quality, including higher copper levels. However, the biological processes and molecular mechanisms involved in copper uptake by Lotus spp. remain poorly understood. Here, we identify four genes that encode putative members of the Lotus copper transporter family, denoted COPT in higher plants. A heterologous functional complementation assay of the Saccharomyces cerevisiae ctr1∆ctr3∆ strain, which lacks the corresponding yeast copper transporters, with the putative Lotus COPT proteins shows a partial rescue of the yeast phenotypes in restrictive media. Under partial submergence conditions, the copper content of L. japonicus plants decreases and the expression of two Lotus COPT genes is induced. These results strongly suggest that the Lotus COPT proteins identified in this work function in copper uptake. In addition, the fact that environmental conditions affect the expression of certain COPT genes supports their involvement in adaptive mechanisms and envisages putative biotechnological strategies to improve cattle copper nutrition.

Spike Timing of Lacunosom-Moleculare Targeting Interneurons and CA3 Pyramidal Cells During High-Frequency Network Oscillations In Vitro

2007 ◽  
Vol 98 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Jay Spampanato ◽  
Istvan Mody
Keyword(s):  
High Frequency ◽  
Epileptiform Activity ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Gamma Oscillations ◽  
Spike Timing ◽  
Network Activity ◽  
Network Oscillations ◽  
Ca3 Pyramidal Cells

Network activity in the 200- to 600-Hz range termed high-frequency oscillations (HFOs) has been detected in epileptic tissue from both humans and rodents and may underlie the mechanism of epileptogenesis in experimental rodent models. Slower network oscillations including theta and gamma oscillations as well as ripples are generated by the complex spike timing and interactions between interneurons and pyramidal cells of the hippocampus. We determined the activity of CA3 pyramidal cells, stratum oriens lacunosum-moleculare (O-LM) and s. radiatum lacunosum-moleculare (R-LM) interneurons during HFO in the in vitro low-Mg2+ model of epileptiform activity in GIN mice. In these animals, interneurons can be identified prior to cell-attached recordings by the expression of green-fluorescent protein (GFP). Simultaneous local field potential recordings from s. pyramidale and on-cell recordings of individual interneurons and principal cells revealed three primary firing behaviors of the active cells: 36% of O-LM interneurons and 60% of pyramidal cells fired action potentials at high frequencies during the HFO. R-LM interneurons were biphasic in that they fired at high frequency at the beginning of the HFO but stopped firing before its end. When considering only the highest frequency component of the oscillations most pyramidal cells fired on the rising phase of the oscillation. These data provide evidence for functional distinction during HFOs within otherwise homogeneous groups of O-LM interneurons and pyramidal cells.

scholarly journals Altered GABAA,slow Inhibition and Network Oscillations in Mice Lacking the GABAA Receptor β3 Subunit

2009 ◽  
Vol 102 (6) ◽  
pp. 3643-3655 ◽  
Author(s):  
Harald Hentschke ◽  
Claudia Benkwitz ◽  
Matthew I. Banks ◽  
Mark G. Perkins ◽  
Gregg E. Homanics ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Gamma Oscillations ◽  
Theta Oscillations ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Gabaergic Inhibition ◽  
Wild Type ◽  
Hippocampal Network

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABAA,fast and GABAA,slow. In hippocampal area CA1, GABAA,fast is generally believed to underlie gamma oscillations, whereas the contribution of GABAA,slow to hippocampal rhythms has been speculative. Hypothesizing that GABAA receptors containing the β3 subunit contribute to GABAA,slow inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABAA receptor β3 subunit-deficient (β3−/−) mice, spontaneous GABAA,slow inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABAA,slow currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing β3 subunits contribute substantially to GABAA,slow currents in pyramidal neurons. By contrast, slow inhibitory control of GABAA,fast-producing interneurons was unaffected in β3−/− mice. In vivo hippocampal network activity was markedly different in the two genotypes. In β3−/− mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency (“nesting”) was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of β3 subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABAA,fast -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity

2010 ◽  
Vol 115 (6) ◽  
pp. 1398-1408 ◽  
Author(s):  
Anne B. Walls ◽  
Linn Hege Nilsen ◽  
Elvar M. Eyjolfsson ◽  
Henrik T. Vestergaard ◽  
Suzanne L. Hansen ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Tonic Inhibition

The CaCTR1 gene is required for high-affinity iron uptake and is transcriptionally controlled by a copper-sensing transactivator encoded by CaMAC1

Microbiology ◽  
2004 ◽  
Vol 150 (7) ◽  
pp. 2197-2208 ◽  
Author(s):  
Marcus E. Marvin ◽  
Robert P. Mason ◽  
Annette M. Cashmore
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Iron Uptake ◽  
Invasive Growth ◽  
Hostile Environment ◽  
Null Mutant ◽  
Copper Uptake ◽  
Similar System ◽  
Copper Transporter ◽  
High Affinity ◽  
Null Strain

The ability of Candida albicans to acquire iron from the hostile environment of the host is known to be necessary for virulence and appears to be achieved using a similar system to that described for Saccharomyces cerevisiae. In S. cerevisiae, high-affinity iron uptake is dependent upon the acquisition of copper. The authors have previously identified a C. albicans gene (CaCTR1) that encodes a copper transporter. Deletion of this gene results in a mutant strain that grows predominantly as pseudohyphae and displays aberrant morphology in low-copper conditions. This paper demonstrates that invasive growth by C. albicans is induced by low-copper conditions and that this is augmented in a Cactr1-null strain. It also shows that deletion of CaCTR1 results in defective iron uptake. In S. cerevisiae, genes that facilitate high-affinity copper uptake are controlled by a copper-sensing transactivator, ScMac1p. The authors have now identified a C. albicans gene (CaMAC1) that encodes a copper-sensing transactivator. A Camac1-null mutant displays phenotypes similar to those of a Cactr1-null mutant and has no detectable CaCTR1 transcripts in low-copper conditions. It is proposed that high-affinity copper uptake by C. albicans is necessary for reductive iron uptake and is transcriptionally controlled by CaMac1p in a similar manner to that in S. cerevisiae.

scholarly journals Polyamine Metabolism under Different Light Regimes in Wheat

2021 ◽  
Vol 22 (21) ◽  
pp. 11717
Author(s):  
Orsolya Kinga Gondor ◽  
Judit Tajti ◽  
Kamirán Áron Hamow ◽  
Imre Majláth ◽  
Gabriella Szalai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fine Tuning ◽  
Polyamine Metabolism ◽  
Light Conditions ◽  
Light Regimes ◽  
Test Light ◽  
Lower Light ◽  
The Relationship ◽  
Back Conversion ◽  
Gene Expression Levels

Although the relationship between polyamines and photosynthesis has been investigated at several levels, the main aim of this experiment was to test light-intensity-dependent influence of polyamine metabolism with or without exogenous polyamines. First, the effect of the duration of the daily illumination, then the effects of different light intensities (50, 250, and 500 μmol m–2 s–1) on the polyamine metabolism at metabolite and gene expression levels were investigated. In the second experiment, polyamine treatments, namely putrescine, spermidine and spermine, were also applied. The different light quantities induced different changes in the polyamine metabolism. In the leaves, light distinctly induced the putrescine level and reduced the 1,3-diaminopropane content. Leaves and roots responded differently to the polyamine treatments. Polyamines improved photosynthesis under lower light conditions. Exogenous polyamine treatments influenced the polyamine metabolism differently under individual light regimes. The fine-tuning of the synthesis, back-conversion and terminal catabolism could be responsible for the observed different polyamine metabolism-modulating strategies, leading to successful adaptation to different light conditions.

scholarly journals CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 322 ◽  
Author(s):  
Ekaterina Ilyechova ◽  
Elisa Bonaldi ◽  
Iurii Orlov ◽  
Ekaterina Skomorokhova ◽  
Ludmila Puchkova ◽  
...  
Keyword(s):  
Cell Line ◽  
Silver Ions ◽  
Nsclc Cell Line ◽  
Double Knockout ◽  
H1299 Cell ◽  
Copper Transporter ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
High Affinity ◽  
Secondary Messenger

Copper, the highly toxic micronutrient, plays two essential roles: it is a catalytic and structural cofactor for Cu-dependent enzymes, and it acts as a secondary messenger. In the cells, copper is imported by CTR1 (high-affinity copper transporter 1), a transmembrane high-affinity copper importer, and DMT1 (divalent metal transporter). In cytosol, enzyme-specific chaperones receive copper from CTR1 C-terminus and deliver it to their apoenzymes. DMT1 cannot be a donor of catalytic copper because it does not have a cytosol domain which is required for copper transfer to the Cu-chaperons that assist the formation of cuproenzymes. Here, we assume that DMT1 can mediate copper way required for a regulatory copper pool. To verify this hypothesis, we used CRISPR/Cas9 to generate H1299 cell line with CTR1 or DMT1 single knockout (KO) and CTR1/DMT1 double knockout (DKO). To confirm KOs of the genes qRT-PCR were used. Two independent clones for each gene were selected for further studies. In CTR1 KO cells, expression of the DMT1 gene was significantly increased and vice versa. In subcellular compartments of the derived cells, copper concentration dropped, however, in nuclei basal level of copper did not change dramatically. CTR1 KO cells, but not DMT1 KO, demonstrated reduced sensitivity to cisplatin and silver ions, the agents that enter the cell through CTR1. Using single CTR1 and DMT1 KO, we were able to show that both, CTR1 and DMT1, provided the formation of vital intracellular cuproenzymes (SOD1, COX), but not secretory ceruloplasmin. The loss of CTR1 resulted in a decrease in the level of COMMD1, XIAP, and NF-κB. Differently, the DMT1 deficiency induced increase of the COMMD1, HIF1α, and XIAP levels. The possibility of using CTR1 KO and DMT1 KO cells to study homeodynamics of catalytic and signaling copper selectively is discussed.

Loss of MeCP2 increases GABA uptake by astrocytes to suppress tonic inhibition of CA1 pyramidal neurons

2021 ◽  
Vol 126 (4) ◽  
pp. 1310-1313
Author(s):  
Brenda M. Milla
Keyword(s):  
Recent Work ◽  
Rett Syndrome ◽  
Pyramidal Neurons ◽  
Neurodevelopmental Disorder ◽  
Tonic Inhibition ◽  
Gaba Uptake ◽  
Gaba Transporter ◽  
Ca1 Pyramidal Neurons

Rett syndrome (RTT) is a neurodevelopmental disorder characterized a spectrum of phenotypes affecting neuronal and glial populations. Recent work by Dong et al. (Dong Q, Kim J, Nguyen L, Bu Q, Chang Q. J Neurosci 40: 6250–6261, 2020) suggests that augmented GABA uptake by astrocytes diminishes tonic inhibition in the hippocampus and contributes to increased seizure propensity in RTT. Here, I will review evidence supporting this possibility and critically evaluate how increased expression of a GABA transporter might contribute to this mechanism.

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