10 results on '"Pannaccione, Anna"'
Search Results
2. A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage
- Author
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Cuomo, Ornella, primary, Gala, Rosaria, additional, Pignataro, Giuseppe, additional, Boscia, Francesca, additional, Secondo, Agnese, additional, Scorziello, Antonella, additional, Pannaccione, Anna, additional, Viggiano, Davide, additional, Adornetto, Annagrazia, additional, Molinaro, Pasquale, additional, Li, Xiao-Fang, additional, Lytton, Jonathan, additional, Di Renzo, Gianfranco, additional, and Annunziato, Lucio, additional
- Published
- 2008
- Full Text
- View/download PDF
3. Targeted Disruption of Na+/Ca2+Exchanger 3 (NCX3) Gene Leads to a Worsening of Ischemic Brain Damage
- Author
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Molinaro, Pasquale, primary, Cuomo, Ornella, additional, Pignataro, Giuseppe, additional, Boscia, Francesca, additional, Sirabella, Rossana, additional, Pannaccione, Anna, additional, Secondo, Agnese, additional, Scorziello, Antonella, additional, Adornetto, Annagrazia, additional, Gala, Rosaria, additional, Viggiano, Davide, additional, Sokolow, Sophie, additional, Herchuelz, Andre, additional, Schurmans, Stèphane, additional, Di Renzo, Gianfranco, additional, and Annunziato, Lucio, additional
- Published
- 2008
- Full Text
- View/download PDF
4. A New Concept: Aß1-42 Generates a Hyperfunctional Proteolytic NCX3 Fragment That Delays Caspase-12 Activation and Neuronal Death.
- Author
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Pannaccione, Anna, Secondo, Agnese, Molinaro, Pasquale, D'Avanzo, Carla, Cantile, Maria, Esposito, Alba, Boscia, Francesca, Scorziello, Antonella, Sirabella, Rossana, Di Renzo, Gianfranco, and Annunziato, Lucio
- Subjects
- *
CASPASES regulation , *ALZHEIMER'S disease , *HOMEOSTASIS , *CALPAIN , *KNOCKOUT mice , *SITE-specific mutagenesis , *PROTEOLYSIS , *ENDOPLASMIC reticulum - Abstract
Although the amyloid-ß1-42 (Aß1-42) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca2+ homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca2+]i), following Aß1-42 exposure, caused the activation of calpain that in turn elicited a cleavage of the Na+/Ca2+ exchanger isoform NCX3. This cleavage generated a hyperfunctional form of the antiporter and increased NCX currents (INCX) in the reverse mode of operation. Interestingly, this NCX3 calpain-dependent cleavage was essential for the Aß1-42-dependent INCX increase. Indeed, the calpain inhibitor calpeptin and the removal of the calpain-cleavage recognition sequence, via site-directed mutagenesis, abolished this effect. Moreover, the enhanced NCX3 activity was paralleled by an increased Ca2+ content in the endoplasmic reticulum (ER) stores. Remarkably, the silencing in PC-12 cells or the knocking-out in mice of the ncx3 gene prevented the enhancement of both INCX and Ca2+ content in ER stores, suggesting that NCX3 was involved in the increase of ER Ca2+ content stimulated by Aß1-42. By contrast, in the late phase (72 h), when the NCX3 proteolytic cleavage abruptly ceased, the occurrence of a parallel reduction in ER Ca2+ content triggered ER stress, as revealed by caspase-12 activation. Concomitantly, the late increase in [Ca2+]i coincided with neuronal death. Interestingly, NCX3 silencing caused an earlier activation of Aß1-42-induced caspase-12. Indeed, in NCX3-silenced neurons, Aß1-42 exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. These results suggest that Aß1-42, through Ca2+-dependent calpain activation, generates a hyperfunctional form of NCX3 that, by increasing Ca2+ content into ER, delays caspase-12 activation and thus neuronal death. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
5. Na+-Ca2+ Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory.
- Author
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Molinaro, Pasquale, Viggiano, Davide, Nisticò, Robert, Sirabella, Rossana, Secondo, Agnese, Boscia, Francesca, Pannaccione, Anna, Scorziello, Antonella, Mehdawy, Bisan, Sokolow, Sophie, Herchuelz, André, Di Renzo, Gianfranco F., and Annunziato, Lucio
- Subjects
HOMEOSTASIS ,NEURONS ,HIPPOCAMPUS (Brain) ,PROTEINS ,MEMORY ,CALCIUM - Abstract
Long-term potentiation (LTP) depends on the coordinated regulation of an ensemble of proteins related to Ca
2+ homeostasis, including Ca2+ transporters. One of the major players in the regulation of intracellular Ca2+ ([Ca2+ ]i ) homeostasis in neurons is the sodium/ calcium exchanger (NCX), which represents the principal mechanism of Ca2+ clearance in the synaptic sites of hippocampal neurons. Because NCX3, one of the three brain isoforms of the NCX family, is highly expressed in the hippocampal subfields involved in LTP, we hypothesized that it might represent a potential candidate forLTPmodulation. To test this hypothesis,wefirst examined the effect of ncx3 gene ablation on NCX currents (INCX ) and Ca2+ homeostasis in hippocampal neurons. ncx3-/- neurons displayed a reduced INCX , a higher basal level of [Ca2+ ]i , and a significantly delayed clearance of [Ca2+ ]i following depolarization. Furthermore, measurement of field EPSPs, recorded from the CA1 area, revealed that ncx3-/- mice had an impaired basal synaptic transmission. Moreover, hippocampal slices from ncx3-/- mice exhibited a worsening in LTP compared with congenic ncx3-/- . Consistently, immunohistochemical and immunoblot analysis indicated that in the hippocampus of ncx3-/- mice both Ca2+ /calmodulin-dependent protein kinase IIα (CaMKIIα) expression and the phospho CaMKIIα/CaMKIIα ratio were significantly reduced compared with ncx3-/- . Interestingly, ncx3-/- mice displayed a reduced spatial learning and memory performance, as revealed by the novel object recognition, Barnes maze, and context-dependent fear conditioning assays. Collectively, our findings demonstrate that the deletion of the ncx3 gene in mice has detrimental consequences on basal synaptic transmission, LTP regulation, spatial learning, and memory performance. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
6. Targeted Disruption of Na+/Ca2+ Exchanger 3 (NCX3) Gene Leads to a Worsening of Ischemic Brain Damage.
- Author
-
Molinaro, Pasquale, Cuomo, Ornella, Pignataro, Giuseppe, Boscia, Francesca, Sirabella, Rossana, Pannaccione, Anna, Secondo, Agnese, Scorziello, Antonella, Adornetto, Annagrazia, Gala, Rosaria, Viggiano, Davide, Sokolow, Sophie, Herchuelz, Andre, Schurmans, Stèphane, Di Renzo, Gianfranco, and Annunziato, Lucio
- Subjects
GENES ,HOMEOSTASIS ,CEREBRAL ischemia ,BRAIN damage ,CEREBROVASCULAR disease - Abstract
Na
+ /Ca+ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na+ and Ca2+ homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3-/-mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3+/+ mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3-/- mice exposed to OGD plus reoxygenation. In addition, in ncx3-/- cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
7. A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage
- Author
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Gianfranco Di Renzo, Rosaria Gala, Francesca Boscia, Lucio Annunziato, Jonathan Lytton, Xiao Fang Li, Pasquale Molinaro, Anna Pannaccione, Davide Viggiano, Antonella Scorziello, Agnese Secondo, Ornella Cuomo, Giuseppe Pignataro, Annagrazia Adornetto, Cuomo, Ornella, Gala, Rosaria, Pignataro, Giuseppe, Boscia, Francesca, Secondo, Agnese, Scorziello, Antonella, Pannaccione, Anna, Viggiano, Davide, Adornetto, Annagrazia, Molinaro, Pasquale, Li, Xf, Lytton, J, DI RENZO, GIANFRANCO MARIA LUIGI, and Annunziato, Lucio
- Subjects
Male ,Gene isoform ,antisense strategy ,medicine.medical_specialty ,Patch-Clamp Techniques ,sodium–calcium exchanger ,Ischemia ,Phosphorothioate Oligonucleotides ,Blood Pressure ,In Vitro Techniques ,cerebral ischemia ,Sodium-Calcium Exchanger ,Brain Ischemia ,Rats, Sprague-Dawley ,Brain ischemia ,Mice ,Ischemic brain ,Internal medicine ,medicine ,Animals ,NCKX ,knock-out ,Cerebral Cortex ,Mice, Knockout ,Neurons ,Analysis of Variance ,Messenger RNA ,Sodium-calcium exchanger ,biology ,Chemistry ,General Neuroscience ,Articles ,Infusion Pumps, Implantable ,medicine.disease ,Potassium-dependent sodium-calcium exchanger ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Cerebrovascular Circulation ,Phosphopyruvate Hydratase ,biology.protein ,Autoradiography ,Calcium ,MCAO ,Blood Gas Analysis ,Neuroscience ,Homeostasis - Abstract
The superfamily of cation/Ca2+plasma–membrane exchangers contains two branches, the K+-independent Na+–Ca2+exchangers (NCXs) and the K+-dependent Na+–Ca2+exchangers (NCKXs), widely expressed in mammals. NCKX2 is the major neuronally expressed isoform among NCKX members. Despite its importance in maintaining Na+, Ca2+, and K+homeostasis in the CNS, the role of NCKX2 during cerebral ischemia, a condition characterized by an alteration of ionic concentrations, has not yet been investigated. The present study examines NCKX2 role in the development of ischemic brain damage in permanent middle cerebral artery occlusion (pMCAO) and transient middle cerebral artery occlusion. Furthermore, to evaluate the effect of nckx2 ablation on neuronal survival,nckx2−/− primary cortical neurons were subjected to oxygen glucose deprivation plus reoxygenation. NCKX2 mRNA and protein expression was evaluated in the ischemic core and surrounding ipsilesional areas, at different time points after pMCAO in rats. In ischemic core and in periinfarctual area, NCKX2 mRNA and protein expression were downregulated. In addition, NCKX2 knock-down by antisense oligodeoxynucleotide and NCKX2 knock-out by genetic disruption dramatically increased infarct volume. Accordingly,nckx2−/− primary cortical neurons displayed a higher vulnerability and a greater [Ca2+]iincrease under hypoxic conditions, compared withnckx2+/+ neurons. In addition, NCKX currents both in the forward and reverse mode of operation were significantly reduced innckx2−/− neurons compared withnckx2+/+ cells. Overall, these results indicate that NCKX2 is involved in brain ischemia, and it may represent a new potential target to be investigated in the study of the molecular mechanisms involved in cerebral ischemia.
- Published
- 2008
8. A new concept: Aβ1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death.
- Author
-
Pannaccione A, Secondo A, Molinaro P, D'Avanzo C, Cantile M, Esposito A, Boscia F, Scorziello A, Sirabella R, Sokolow S, Herchuelz A, Di Renzo G, and Annunziato L
- Subjects
- Animals, Calcium metabolism, Calcium Channel Blockers pharmacology, Calpain metabolism, Cell Death drug effects, Cell Death genetics, Cell Differentiation drug effects, Cells, Cultured, Chelating Agents pharmacology, Cricetinae, Dogs, Dose-Response Relationship, Drug, Egtazic Acid pharmacology, Embryo, Mammalian, Endoplasmic Reticulum drug effects, Enzyme Activation drug effects, Female, Hippocampus cytology, Male, Mice, Mice, Knockout, Nerve Growth Factor pharmacology, Patch-Clamp Techniques, RNA Interference physiology, Rats, Sodium metabolism, Sodium-Calcium Exchanger genetics, Time Factors, Transfection, Up-Regulation drug effects, Up-Regulation genetics, Amyloid beta-Peptides pharmacology, Caspase 3 metabolism, Neurons drug effects, Peptide Fragments pharmacology, Proteolysis drug effects, Sodium-Calcium Exchanger metabolism
- Abstract
Although the amyloid-β(1-42) (Aβ(1-42)) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca(2+) homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca(2+)](i)), following Aβ(1-42) exposure, caused the activation of calpain that in turn elicited a cleavage of the Na(+)/Ca(2+) exchanger isoform NCX3. This cleavage generated a hyperfunctional form of the antiporter and increased NCX currents (I(NCX)) in the reverse mode of operation. Interestingly, this NCX3 calpain-dependent cleavage was essential for the Aβ(1-42)-dependent I(NCX) increase. Indeed, the calpain inhibitor calpeptin and the removal of the calpain-cleavage recognition sequence, via site-directed mutagenesis, abolished this effect. Moreover, the enhanced NCX3 activity was paralleled by an increased Ca(2+) content in the endoplasmic reticulum (ER) stores. Remarkably, the silencing in PC-12 cells or the knocking-out in mice of the ncx3 gene prevented the enhancement of both I(NCX) and Ca(2+) content in ER stores, suggesting that NCX3 was involved in the increase of ER Ca(2+) content stimulated by Aβ(1-42). By contrast, in the late phase (72 h), when the NCX3 proteolytic cleavage abruptly ceased, the occurrence of a parallel reduction in ER Ca(2+) content triggered ER stress, as revealed by caspase-12 activation. Concomitantly, the late increase in [Ca(2+)](i) coincided with neuronal death. Interestingly, NCX3 silencing caused an earlier activation of Aβ(1-42)-induced caspase-12. Indeed, in NCX3-silenced neurons, Aβ(1-42) exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. These results suggest that Aβ(1-42), through Ca(2+)-dependent calpain activation, generates a hyperfunctional form of NCX3 that, by increasing Ca(2+) content into ER, delays caspase-12 activation and thus neuronal death.
- Published
- 2012
- Full Text
- View/download PDF
9. Na+ -Ca2+ exchanger (NCX3) knock-out mice display an impairment in hippocampal long-term potentiation and spatial learning and memory.
- Author
-
Molinaro P, Viggiano D, Nisticò R, Sirabella R, Secondo A, Boscia F, Pannaccione A, Scorziello A, Mehdawy B, Sokolow S, Herchuelz A, Di Renzo GF, and Annunziato L
- Subjects
- Animals, Cells, Cultured, Gene Silencing, Hippocampus metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Sodium-Calcium Exchanger metabolism, Synaptic Transmission genetics, Hippocampus physiopathology, Long-Term Potentiation genetics, Maze Learning physiology, Memory physiology, Sodium-Calcium Exchanger genetics, Spatial Behavior physiology
- Abstract
Long-term potentiation (LTP) depends on the coordinated regulation of an ensemble of proteins related to Ca(2+) homeostasis, including Ca(2+) transporters. One of the major players in the regulation of intracellular Ca(2+) ([Ca(2+)](i)) homeostasis in neurons is the sodium/calcium exchanger (NCX), which represents the principal mechanism of Ca(2+) clearance in the synaptic sites of hippocampal neurons. Because NCX3, one of the three brain isoforms of the NCX family, is highly expressed in the hippocampal subfields involved in LTP, we hypothesized that it might represent a potential candidate for LTP modulation. To test this hypothesis, we first examined the effect of ncx3 gene ablation on NCX currents (I(NCX)) and Ca(2+) homeostasis in hippocampal neurons. ncx3(-/-) neurons displayed a reduced I(NCX), a higher basal level of [Ca(2+)](i), and a significantly delayed clearance of [Ca(2+)](i) following depolarization. Furthermore, measurement of field EPSPs, recorded from the CA1 area, revealed that ncx3(-/-) mice had an impaired basal synaptic transmission. Moreover, hippocampal slices from ncx3(-/-) mice exhibited a worsening in LTP compared with congenic ncx3(+/+). Consistently, immunohistochemical and immunoblot analysis indicated that in the hippocampus of ncx3(-/-) mice both Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) expression and the phosphoCaMKIIα/CaMKIIα ratio were significantly reduced compared with ncx3(+/+). Interestingly, ncx3(-/-) mice displayed a reduced spatial learning and memory performance, as revealed by the novel object recognition, Barnes maze, and context-dependent fear conditioning assays. Collectively, our findings demonstrate that the deletion of the ncx3 gene in mice has detrimental consequences on basal synaptic transmission, LTP regulation, spatial learning, and memory performance.
- Published
- 2011
- Full Text
- View/download PDF
10. Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage.
- Author
-
Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, and Annunziato L
- Subjects
- Animals, Brain Ischemia metabolism, Cell Death genetics, Cell Death physiology, Cell Survival genetics, Cell Survival physiology, Disease Progression, Hippocampus metabolism, Hippocampus pathology, Homeostasis genetics, Homeostasis physiology, Hypoxia, Brain genetics, Hypoxia, Brain metabolism, Hypoxia, Brain pathology, Membrane Transport Proteins deficiency, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Neurons metabolism, Neurons pathology, Organ Culture Techniques, Signal Transduction genetics, Signal Transduction physiology, Brain Ischemia genetics, Brain Ischemia pathology, Gene Targeting methods, Membrane Transport Proteins genetics, Sodium-Calcium Exchanger antagonists & inhibitors, Sodium-Calcium Exchanger genetics
- Abstract
Na+/Ca+ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na+ and Ca2+ homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3-/- mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3-/- mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3-/- mice exposed to OGD plus reoxygenation. In addition, in ncx3-/- cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.
- Published
- 2008
- Full Text
- View/download PDF
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