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Keywords = glutamate exocytosis

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14 pages, 1820 KiB  
Article
DYRK1A Up-Regulation Specifically Impairs a Presynaptic Form of Long-Term Potentiation
by Aude-Marie Lepagnol-Bestel, Simon Haziza, Julia Viard, Paul A. Salin, Arnaud Duchon, Yann Herault and Michel Simonneau
Life 2025, 15(2), 149; https://doi.org/10.3390/life15020149 - 22 Jan 2025
Viewed by 1005
Abstract
Chromosome 21 DYRK1A kinase is associated with a variety of neuronal diseases including Down syndrome. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated YAC 152F7 (570 kb), encoding six chromosome 21 [...] Read more.
Chromosome 21 DYRK1A kinase is associated with a variety of neuronal diseases including Down syndrome. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated YAC 152F7 (570 kb), encoding six chromosome 21 genes including DYRK1A. The 152F7 mice displayed learning difficulties but their N-methyl-D-aspartate (NMDA)-dependent synaptic long-term potentiation is indistinguishable from non-transgenic animals. We have demonstrated that a presynaptic form of NMDA-independent long-term potentiation (LTP) at the hippocampal mossy fiber was impaired in the 152F7 animals. To obtain insights into the molecular mechanisms involved in such synaptic changes, we analyzed the Dyrk1a interactions with chromatin remodelers. We found that the number of DYRK1A-EP300 and DYRK1A-CREBPP increased in 152F7 mice. Moreover, we observed a transcriptional decrease in genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2 and Rab3A.To refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicates the gene Dyrk1a. Again, we found that this NMDA-independent form of LTP is impaired in this mouse line. Altogether, our results demonstrate that Dyrk1a up-regulation is sufficient to specifically inhibit the NMDA-independent form of LTP and suggest that this inhibition is linked to chromatin changes that deregulate genes encoding proteins involved in glutamate synaptic release. Full article
(This article belongs to the Section Medical Research)
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14 pages, 2440 KiB  
Review
Effects of Calcium Ion Dyshomeostasis and Calcium Ion-Induced Excitotoxicity in Parkinson’s Disease
by Daleum Nam, Hyejung Kim, Sun Jung Han, Ilhong Son and Dong Hwan Ho
J. Mol. Pathol. 2024, 5(4), 544-557; https://doi.org/10.3390/jmp5040037 - 14 Dec 2024
Cited by 1 | Viewed by 1660
Abstract
Calcium ions (Ca2+) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of [...] Read more.
Calcium ions (Ca2+) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of excitotoxicity, the excessive release of glutamate in the synapses can trigger the activation of postsynaptic receptors. Upon activation, Ca2+ influx into the cell from the extracellular space via their associated ion channels, most notably L-type Ca2+ channels. Previous studies have indicated that α-synuclein (α-syn), a typical cytosolic protein, plays a significant role in the pathogenesis of Parkinson’s disease (PD). It is also worth noting that the aggregated form of α-syn has the capacity to affect Ca2+ homeostasis by altering the function of Ca2+ regulation. The upregulation of leucine-rich repeat kinase 2 (LRRK2) is closely associated with PD pathogenesis. LRRK2 mutants exhibit a dysregulation of calcium signaling, resulting in dopaminergic neuronal degeneration. It could therefore be proposed that α-syn and LRRK2 play important roles in the mechanisms underlying Ca2+ dyshomeostasis and excitotoxicity in PD. Full article
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20 pages, 4631 KiB  
Article
Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats
by Cheng-Wei Lu, Tzu-Yu Lin, Kuan-Ming Chiu, Ming-Yi Lee and Su-Jane Wang
Biomolecules 2024, 14(5), 589; https://doi.org/10.3390/biom14050589 - 16 May 2024
Cited by 7 | Viewed by 1751
Abstract
Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside XVII (GP-17), a gypenoside monomer, on the glutamatergic system. In vitro, in rat cortical nerve terminals (synaptosomes), GP-17 [...] Read more.
Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside XVII (GP-17), a gypenoside monomer, on the glutamatergic system. In vitro, in rat cortical nerve terminals (synaptosomes), GP-17 dose-dependently decreased glutamate release with an IC50 value of 16 μM. The removal of extracellular Ca2+ or blockade of N-and P/Q-type Ca2+ channels and protein kinase A (PKA) abolished the inhibitory effect of GP-17 on glutamate release from cortical synaptosomes. GP-17 also significantly reduced the phosphorylation of PKA, SNAP-25, and synapsin I in cortical synaptosomes. In an in vivo rat model of glutamate excitotoxicity induced by kainic acid (KA), GP-17 pretreatment significantly prevented seizures and rescued neuronal cell injury and glutamate elevation in the cortex. GP-17 pretreatment decreased the expression levels of sodium-coupled neutral amino acid transporter 1, glutamate synthesis enzyme glutaminase and vesicular glutamate transporter 1 but increased the expression level of glutamate metabolism enzyme glutamate dehydrogenase in the cortex of KA-treated rats. In addition, the KA-induced alterations in the N-methyl-D-aspartate receptor subunits GluN2A and GluN2B in the cortex were prevented by GP-17 pretreatment. GP-17 also prevented the KA-induced decrease in cerebral blood flow and arginase II expression. These results suggest that (i) GP-17, through the suppression of N- and P/Q-type Ca2+ channels and consequent PKA-mediated SNAP-25 and synapsin I phosphorylation, reduces glutamate exocytosis from cortical synaptosomes; and (ii) GP-17 has a neuroprotective effect on KA-induced glutamate excitotoxicity in rats through regulating synaptic glutamate release and cerebral blood flow. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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15 pages, 3775 KiB  
Article
Phillygenin Suppresses Glutamate Exocytosis in Rat Cerebrocortical Nerve Terminals (Synaptosomes) through the Inhibition of Cav2.2 Calcium Channels
by Ming-Yi Lee, Tzu-Yu Lin, Ya-Ying Chang, Kuan-Ming Chiu and Su-Jane Wang
Biomedicines 2024, 12(3), 495; https://doi.org/10.3390/biomedicines12030495 - 22 Feb 2024
Viewed by 1724
Abstract
Glutamate is a major excitatory neurotransmitter that mediates neuronal damage in acute and chronic brain disorders. The effect and mechanism of phillygenin, a natural compound with neuroprotective potential, on glutamate release in isolated nerve terminals (synaptosomes) prepared from the rat cerebral cortex were [...] Read more.
Glutamate is a major excitatory neurotransmitter that mediates neuronal damage in acute and chronic brain disorders. The effect and mechanism of phillygenin, a natural compound with neuroprotective potential, on glutamate release in isolated nerve terminals (synaptosomes) prepared from the rat cerebral cortex were examined. In this study, 4-aminopyridine (4-AP), a potassium channel blocker, was utilized to induce the release of glutamate, which was subsequently quantified via a fluorometric assay. Our findings revealed that phillygenin reduced 4-AP-induced glutamate release, and this inhibitory effect was reversed by removing extracellular Ca2+ or inhibiting vesicular transport with bafilomycin A1. However, exposure to the glutamate transporter inhibitor dl-threo-beta-benzyl-oxyaspartate (dl-TOBA) did not influence the inhibitory effect. Moreover, phillygenin did not change the synaptosomal membrane potential but lowered the 4-AP-triggered increase in intrasynaptosomal Ca2+ concentration ([Ca2+]i). Antagonizing Cav2.2 (N-type) calcium channels blocked the inhibition of glutamate release by phillygenin, whereas pretreatment with the mitochondrial Na+/Ca2+ exchanger inhibitor, CGP37157 or the ryanodine receptor inhibitor, dantrolene, both of which block intracellular Ca2+ release, had no effect. The effect of phillygenin on glutamate release triggered by 4-AP was completely abolished when MAPK/ERK inhibitors were applied. Furthermore, phillygenin attenuated the phosphorylation of ERK1/2 and its major presynaptic target, synapsin I, a protein associated with synaptic vesicles. These data collectively suggest that phillygenin mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through Cav2.2 calcium channels, thereby subsequently suppressing the MAPK/ERK/synapsin I signaling cascade. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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20 pages, 10139 KiB  
Article
Presynaptic Release-Regulating Sphingosine 1-Phosphate 1/3 Receptors in Cortical Glutamatergic Terminals: Adaptations in EAE Mice and Impact of Therapeutic FTY720
by Alessandra Roggeri, Guendalina Olivero, Cesare Usai, Tim Vanmierlo and Anna Pittaluga
Cells 2023, 12(19), 2343; https://doi.org/10.3390/cells12192343 - 24 Sep 2023
Cited by 3 | Viewed by 1599
Abstract
This study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1–30 nM) inhibits the 12 mM [...] Read more.
This study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1–30 nM) inhibits the 12 mM KCl-evoked glutamate exocytosis (quantified as the release of [3H]D-aspartate) while the S1P3R allosteric agonist CYM-5541 potentiates it and (ii) these effects are inhibited by the S1P1R antagonist Ex 26 (30–300 nM) and the S1P3R antagonist TY-52156 (100–1000 nM), respectively. Confocal microscopy and western blot analysis confirmed the presence of S1P1R and S1P3R proteins in cortical glutamatergic synaptosomes, which were scarcely accessible to biotin in a biotinylation study. Then, we demonstrated that S1P1R and S1P3R densities and their release activity are amplified in cortical synaptosomes of mice suffering from experimental autoimmune encephalomyelitis (EAE), despite receptors maintain their preferential internal distribution. Receptor changes recover following chronic oral therapeutic FTY720 (0.03 mg/Kg/day). These results improve our knowledge of the role of presynaptic release-regulating S1P1Rs and S1P3Rs controlling glutamate transmission in the CNS also unravelling functional adaptations during EAE that recover following chronic FTY720. In a whole, these findings provide new information on the central neuroprotectant activities of FTY720. Full article
(This article belongs to the Section Cells of the Nervous System)
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16 pages, 1180 KiB  
Review
Insights on the Multifaceted Roles of Wild-Type and Mutated Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis Pathogenesis
by Valentina Rubino, Giuliana La Rosa, Luca Pipicelli, Flavia Carriero, Simona Damiano, Mariarosaria Santillo, Giuseppe Terrazzano, Giuseppina Ruggiero and Paolo Mondola
Antioxidants 2023, 12(9), 1747; https://doi.org/10.3390/antiox12091747 - 10 Sep 2023
Cited by 4 | Viewed by 2577
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, due to excessive glutamate levels and increased intracellular Ca2+ concentration, has also been proposed to play a key role in ALS pathogenesis/progression. Reactive Oxygen Species (ROS) behave as key second messengers for multiple receptor/ligand interactions. ROS-dependent regulatory networks are usually mediated by peroxides. Superoxide Dismutase 1 (SOD1) physiologically mediates intracellular peroxide generation. About 10% of ALS subjects show a familial disease associated with different gain-of-function SOD1 mutations. The occurrence of sporadic ALS, not clearly associated with SOD1 defects, has been also described. SOD1-dependent pathways have been involved in neuron functional network as well as in immune-response regulation. Both, neuron depolarization and antigen-dependent T-cell activation mediate SOD1 exocytosis, inducing increased interaction of the enzyme with a complex molecular network involved in the regulation of neuron functional activity and immune response. Here, alteration of SOD1-dependent pathways mediating increased intracellular Ca2+ levels, altered mitochondria functions and defective inflammatory process regulation have been proposed to be relevant for ALS pathogenesis/progression. Full article
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11 pages, 1302 KiB  
Review
Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes
by Jorge Tamarit-Rodriguez
Metabolites 2023, 13(6), 697; https://doi.org/10.3390/metabo13060697 - 27 May 2023
Cited by 7 | Viewed by 2548
Abstract
The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that [...] Read more.
The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K+-channel at the plasma membrane. The resultant depolarization of the β-cells opens voltage-dependent Ca2+-channels at the plasma membrane that triggers the exocytosis of insulin secretory granules. The secretory response is biphasic with a first and transient peak followed by a sustained phase. The first phase is reproduced by a depolarization of the β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide (triggering phase); the sustained phase (amplifying phase) depends on the participation of metabolic signals that remain to be determined. Our group has been investigating for several years the participation of the β-cell GABA metabolism in the stimulation of insulin secretion by three different secretagogues (glucose, a mixture of L-leucine plus L-glutamine, and some branched chain alpha-ketoacids, BCKAs). They stimulate a biphasic secretion of insulin accompanied by a strong suppression of the intracellular islet content of gamma-aminobutyric acid (GABA). As the islet GABA release simultaneously decreased, it was concluded that this resulted from an increased GABA shunt metabolism. The entrance of GABA into the shunt is catalyzed by GABA transaminase (GABAT) that transfers an amino group between GABA and alpha-ketoglutarate, resulting in succinic acid semialdehyde (SSA) and L-glutamate. SSA is oxidized to succinic acid that is further oxidized in the citric acid cycle. Inhibitors of GABAT (gamma-vinyl GABA, gabaculine) or glutamic acid decarboxylating activity (GAD), allylglycine, partially suppress the secretory response as well as GABA metabolism and islet ATP content and the ATP/ADP ratio. It is concluded that the GABA shunt metabolism contributes together with the own metabolism of metabolic secretagogues to increase islet mitochondrial oxidative phosphorylation. These experimental findings emphasize that the GABA shunt metabolism is a previously unrecognized anaplerotic mitochondrial pathway feeding the citric acid cycle with a β-cell endogenous substrate. It is therefore a postulated alternative to the proposed mitochondrial cataplerotic pathway(s) responsible for the amplification phase of insulin secretion. It is concluded the new postulated alternative suggests a possible new mechanism of β-cell degradation in type 2 (perhaps also in type 1) diabetes. Full article
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17 pages, 2808 KiB  
Article
Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex
by Cheng-Wei Lu, Chia-Chan Wu, Kuan-Ming Chiu, Ming-Yi Lee, Tzu-Yu Lin and Su-Jane Wang
Int. J. Mol. Sci. 2022, 23(21), 13406; https://doi.org/10.3390/ijms232113406 - 2 Nov 2022
Cited by 11 | Viewed by 2719
Abstract
The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia [...] Read more.
The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia argyi, affected glutamate release in rat cortical nerve terminals (synaptosomes). Additionally, we evaluated the effect of eupatilin in an animal model of kainic acid (KA) excitotoxicity, particularly on the levels of glutamate and N-methyl-D-aspartate (NMDA) receptor subunits (GluN2A and GluN2B). We found that eupatilin decreased depolarization-evoked glutamate release from rat cortical synaptosomes and that this effect was accompanied by a reduction in cytosolic Ca2+ elevation, inhibition of P/Q-type Ca2+ channels, decreased synapsin I Ca2+-dependent phosphorylation and no detectable effect on the membrane potential. In a KA-induced glutamate excitotoxicity rat model, the administration of eupatilin before KA administration prevented neuronal cell degeneration, glutamate elevation, glutamate-generating enzyme glutaminase increase, excitatory amino acid transporter (EAAT) decrease, GluN2A protein decrease and GluN2B protein increase in the rat cortex. Taken together, the results suggest that eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca2+ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by KA by preventing glutamatergic alterations in the rat cortex. Thus, this study suggests that eupatilin can be considered a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity. Full article
(This article belongs to the Special Issue Biological Properties of Medicinal Plants)
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16 pages, 1570 KiB  
Article
Presynaptic 5-HT2A-mGlu2/3 Receptor–Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis
by Alice Taddeucci, Guendalina Olivero, Alessandra Roggeri, Claudio Milanese, Francesco Paolo Di Giorgio, Massimo Grilli, Mario Marchi, Beatrice Garrone and Anna Pittaluga
Cells 2022, 11(19), 3035; https://doi.org/10.3390/cells11193035 - 28 Sep 2022
Cited by 9 | Viewed by 4454
Abstract
The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant [...] Read more.
The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 μM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 μM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1–10 μM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 μM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens. Full article
(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)
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16 pages, 3064 KiB  
Article
The Effect of Isosaponarin Derived from Wasabi Leaves on Glutamate Release in Rat Synaptosomes and Its Underlying Mechanism
by Cheng-Wei Lu, Kun-Chieh Yeh, Kuan-Ming Chiu, Ming-Yi Lee, Tzu-Yu Lin and Su-Jane Wang
Int. J. Mol. Sci. 2022, 23(15), 8752; https://doi.org/10.3390/ijms23158752 - 6 Aug 2022
Cited by 11 | Viewed by 2720
Abstract
Excessive glutamate release is known to be involved in the pathogenesis of neurological diseases, and suppression of glutamate release from nerve terminals is considered to be a treatment strategy. In this study, we investigated whether isosaponarin, a flavone glycoside isolated from wasabi leaves, [...] Read more.
Excessive glutamate release is known to be involved in the pathogenesis of neurological diseases, and suppression of glutamate release from nerve terminals is considered to be a treatment strategy. In this study, we investigated whether isosaponarin, a flavone glycoside isolated from wasabi leaves, could affect glutamate release in rat cerebral cortex nerve terminals (synaptosomes). The release of glutamate was evoked by the K+ channel blocker 4-aminopyridine (4-AP) and measured by an online enzyme-coupled fluorimetric assay. Isosaponarin produced a concentration-dependent inhibition of 4-AP-evoked glutamate release with a half-maximum inhibition of release value of 22 μM. The inhibition caused by isosaponarin was prevented by eliminating extracellular Ca2+ or by using bafilomycin A1, an inhibitor of synaptic vesicle exocytosis. Isosaponarin decreased intrasynaptosomal rises in Ca2+ levels that were induced by 4-AP, without affecting the synaptosomal membrane potential. The isosaponarin-induced inhibition of glutamate release was significantly prevented in synaptosomes that were pretreated with a combination of the calcium channel blockers ω-conotoxin GVIA (N-type) and ω-agatoxin IVA (P/Q-types). The protein kinase C (PKC) pan-inhibitor GF109203X and the Ca2+-dependent PKC inhibitor Go6976 abolished the inhibition of glutamate release by isosaponarin, while the Ca2+-independent PKC inhibitor rottlerin did not show any effect. The results from immunoblotting assays also showed that isosaponarin lowered PKC, PKCα, synaptosomal-associated protein of 25 kDa (SNAP-25), and myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation induced by 4-AP. In addition, FM1-43-labeled synaptic vesicles in synaptosomes showed that treatment with isosaponarin resulted in an attenuation of the 4-AP-induced decrease in fluorescence intensity that is consistent with glutamate release. Transmission electron microscopy of synaptosomes also provided evidence that isosaponarin altered the number of synaptic vesicles. These results indicate that isosaponarin suppresses the Ca2+-dependent PKC/SNAP-25 and MARCKS pathways in synaptosomes, causing a decrease in the number of available synaptic vesicles, which inhibits vesicular glutamate release from synaptosomes. Full article
(This article belongs to the Special Issue Biological Properties of Medicinal Plants)
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26 pages, 14241 KiB  
Review
Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders
by Sairaj Satarker, Sree Lalitha Bojja, Prasada Chowdari Gurram, Jayesh Mudgal, Devinder Arora and Madhavan Nampoothiri
Cells 2022, 11(7), 1139; https://doi.org/10.3390/cells11071139 - 28 Mar 2022
Cited by 53 | Viewed by 11329
Abstract
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several [...] Read more.
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value. Full article
(This article belongs to the Special Issue Glutamatergic Transmission: Role of Astrocytes in Health and Disease)
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15 pages, 1419 KiB  
Review
Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System
by Anna Pittaluga, Alessandra Roggeri, Giulia Vallarino and Guendalina Olivero
Int. J. Mol. Sci. 2021, 22(11), 5864; https://doi.org/10.3390/ijms22115864 - 30 May 2021
Cited by 18 | Viewed by 4590
Abstract
Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca2+ dependent manner upon application [...] Read more.
Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca2+ dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through “volume diffusion”, a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of “volume diffusion” and in the “receptor-receptor interaction” unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders. Full article
(This article belongs to the Special Issue Somatostatin 2.0)
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13 pages, 1311 KiB  
Review
The Function of Sialidase Revealed by Sialidase Activity Imaging Probe
by Akira Minami, Yuuki Kurebayashi, Tadanobu Takahashi, Tadamune Otsubo, Kiyoshi Ikeda and Takashi Suzuki
Int. J. Mol. Sci. 2021, 22(6), 3187; https://doi.org/10.3390/ijms22063187 - 20 Mar 2021
Cited by 10 | Viewed by 5862
Abstract
Sialidase cleaves sialic acid residues from glycans such as glycoproteins and glycolipids. In the brain, desorption of the sialic acid by sialidase is essential for synaptic plasticity, learning and memory and synaptic transmission. BTP3-Neu5Ac has been developed for sensitive imaging of sialidase enzyme [...] Read more.
Sialidase cleaves sialic acid residues from glycans such as glycoproteins and glycolipids. In the brain, desorption of the sialic acid by sialidase is essential for synaptic plasticity, learning and memory and synaptic transmission. BTP3-Neu5Ac has been developed for sensitive imaging of sialidase enzyme activity in mammalian tissues. Sialidase activity in the rat hippocampus detected with BTP3-Neu5Ac increases rapidly by neuronal depolarization. It is presumed that an increased sialidase activity in conjunction with neural excitation is involved in the formation of the neural circuit for memory. Since sialidase inhibits the exocytosis of the excitatory neurotransmitter glutamate, the increased sialidase activity by neural excitation might play a role in the negative feedback mechanism against the glutamate release. Mammalian tissues other than the brain have also been stained with BTP3-Neu5Ac. On the basis of information on the sialidase activity imaging in the pancreas, it was found that sialidase inhibitor can be used as an anti-diabetic drug that can avoid hypoglycemia, a serious side effect of insulin secretagogues. In this review, we discuss the role of sialidase in the brain as well as in the pancreas and skin, as revealed by using a sialidase activity imaging probe. We also present the detection of influenza virus with BTP3-Neu5Ac and modification of BTP3-Neu5Ac. Full article
(This article belongs to the Special Issue Function and Expression of Neural Glycans)
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31 pages, 24183 KiB  
Article
Orthosiphon stamineus Proteins Alleviate Pentylenetetrazol-Induced Seizures in Zebrafish
by Yin-Sir Chung, Brandon Kar Meng Choo, Pervaiz Khalid Ahmed, Iekhsan Othman and Mohd. Farooq Shaikh
Biomedicines 2020, 8(7), 191; https://doi.org/10.3390/biomedicines8070191 - 2 Jul 2020
Cited by 15 | Viewed by 3753
Abstract
The anticonvulsive potential of proteins extracted from Orthosiphon stamineus leaves (OSLP) has never been elucidated in zebrafish (Danio rerio). This study thus aims to elucidate the anticonvulsive potential of OSLP in pentylenetetrazol (PTZ)-induced seizure model. Physical changes (seizure score and seizure [...] Read more.
The anticonvulsive potential of proteins extracted from Orthosiphon stamineus leaves (OSLP) has never been elucidated in zebrafish (Danio rerio). This study thus aims to elucidate the anticonvulsive potential of OSLP in pentylenetetrazol (PTZ)-induced seizure model. Physical changes (seizure score and seizure onset time, behavior, locomotor) and neurotransmitter analysis were elucidated to assess the pharmacological activity. The protective mechanism of OSLP on brain was also studied using mass spectrometry-based label-free proteomic quantification (LFQ) and bioinformatics. OSLP was found to be safe up to 800 µg/kg and pre-treatment with OSLP (800 µg/kg, i.p., 30 min) decreased the frequency of convulsive activities (lower seizure score and prolonged seizure onset time), improved locomotor behaviors (reduced erratic swimming movements and bottom-dwelling habit), and lowered the excitatory neurotransmitter (glutamate). Pre-treatment with OSLP increased protein Complexin 2 (Cplx 2) expression in the zebrafish brain. Cplx2 is an important regulator in the trans-SNARE complex which is required during the vesicle priming phase in the calcium-dependent synaptic vesicle exocytosis. Findings in this study collectively suggests that OSLP could be regulating the release of neurotransmitters via calcium-dependent synaptic vesicle exocytosis mediated by the “Synaptic Vesicle Cycle” pathway. OSLP’s anticonvulsive actions could be acting differently from diazepam (DZP) and with that, it might not produce the similar cognitive insults such as DZP. Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease 2.0)
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18 pages, 2232 KiB  
Article
Chemically Functionalized Water-Soluble Single-Walled Carbon Nanotubes Obstruct Vesicular/Plasmalemmal Recycling in Astrocytes Down-Stream of Calcium Ions
by Manoj K. Gottipati, Elena Bekyarova, Robert C. Haddon and Vladimir Parpura
Cells 2020, 9(7), 1597; https://doi.org/10.3390/cells9071597 - 1 Jul 2020
Cited by 3 | Viewed by 2693
Abstract
We used single-walled carbon nanotubes chemically functionalized with polyethylene glycol (SWCNT-PEG) to assess the effects of this nanomaterial on astrocytic endocytosis and exocytosis. We observed that the SWCNT-PEG do not affect the adenosine triphosphate (ATP)-evoked Ca2+ elevations in astrocytes but significantly reduce [...] Read more.
We used single-walled carbon nanotubes chemically functionalized with polyethylene glycol (SWCNT-PEG) to assess the effects of this nanomaterial on astrocytic endocytosis and exocytosis. We observed that the SWCNT-PEG do not affect the adenosine triphosphate (ATP)-evoked Ca2+ elevations in astrocytes but significantly reduce the Ca2+-dependent glutamate release. There was a significant decrease in the endocytic load of the recycling dye during constitutive and ATP-evoked recycling. Furthermore, SWCNT-PEG hampered ATP-evoked exocytotic release of the loaded recycling dye. Thus, by functionally obstructing evoked vesicular recycling, SWCNT-PEG reduced glutamate release from astrocytes via regulated exocytosis. These effects implicate SWCNT-PEG as a modulator of Ca2+-dependent exocytosis in astrocytes downstream of Ca2+, likely at the level of vesicle fusion with/pinching off the plasma membrane. Full article
(This article belongs to the Special Issue Astrocytes in Space and Time)
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