A New Concept: A 1-42 Generates a Hyperfunctional Proteolytic NCX3 Fragment That Delays Caspase-12 Activation and Neuronal Death

Pannaccione, Anna; Secondo, Agnese; Molinaro, Pasquale; D’Avanzo, Carla; Cantile, Monica; Esposito, Alba; Boscia, Francesca; Scorziello, Antonella; Sirabella, Rossana; Renzo, Gianfranco Di; Annunziato, Lucio

doi:10.1523/jneurosci.6429-11.2012

Cited by 67 publications

(77 citation statements)

References 53 publications

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“…Lysine 590 might represent the SUMO1 posttranslational modification site on NCX3. Interestingly, this residue is located in the main cytosolic f-loop, a region involved in the regulation of NCX stability and activity, 31,32 thus suggesting that NCX3 sumoylation might influence the stability of the antiporter. Indeed, an important aspect emerging from this article is that after SUMO1 silencing, a downregulation of NCX3 protein levels occurred during tMCAO and preconditioning+tMCAO, thus indicating that a decrease in SUMO1-mediated protection of NCX3 from degradation may occur.…”

Section: Discussionmentioning

confidence: 99%

Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning

Cuomo

Pignataro

Sirabella

et al. 2016

Stroke

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Background and Purpose— The small ubiquitin-like modifier (SUMO), a ubiquitin-like protein involved in posttranslational protein modifications, is activated by several conditions, such as heat stress, hypoxia, and hibernation and confers neuroprotection. Sumoylation enzymes and substrates are expressed also at the plasma membrane level. Among the numerous plasma membrane proteins controlling ionic homeostasis during cerebral ischemia, 1 of the 3 brain sodium/calcium exchangers (NCX3), exerts a protective role during ischemic preconditioning. In this study, we evaluated whether NCX3 is a target for sumoylation and whether this posttranslational modification participates in ischemic preconditioning-induced neuroprotection. To test these hypotheses, we analyzed (1) SUMO1 conjugation pattern after ischemic preconditioning; (2) the effect of SUMO1 knockdown on the ischemic damage after transient middle cerebral artery occlusion and ischemic preconditioning, (3) the possible interaction between SUMO1 and NCX3 and (4) the molecular determinants of NCX3 sequence responsible for sumoylation. Methods— Focal brain ischemia and ischemic preconditioning were induced in rats by middle cerebral artery occlusion. SUMOylation was evaluated by western blot and immunohistochemistry. SUMO1 and NCX3 interaction was analyzed by site-directed mutagenesis and immunoprecipitation assay. Results— We found that (1) SUMO1 knockdown worsened ischemic damage and reduced the protective effect of preconditioning; (2) SUMO1 bound to NCX3 at lysine residue 590, and its silencing increased NCX3 degradation; and (3) NCX3 sumoylation participates in SUMO1 protective role during ischemic preconditioning. Thus, our results demonstrate that NCX3 sumoylation confers additional neuroprotection in ischemic preconditioning. Conclusions— Finally, this study suggests that NCX3 sumoylation might be a new target to enhance ischemic preconditioning-induced neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning

Cuomo

Pignataro

Sirabella

et al. 2016

Stroke

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“…I NCX was recorded from differentiated PC12 cells with the whole-cell patch clamp technique (22). Currents were filtered at 5 kHz and digitized with a Digidata 1322A interface (Molecular Devices).…”

Section: Electrophysiological Recording Of Ncx and Voltage-gated Sodimentioning

confidence: 99%

Involvement of the Na+/Ca2+ exchanger isoform 1 (NCX1) in Neuronal Growth Factor (NGF)-induced Neuronal Differentiation through Ca2+-dependent Akt Phosphorylation

Secondo

Esposito

Sirabella

et al. 2015

Journal of Biological Chemistry

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“…3 These exchangers are all present in neurons, astrocytes, oligodendrocytes, and microglia where they play a relevant role in maintaining Na þ and Ca 2þ homeostasis under different neurophysiological 4,5 and neuropathological conditions. [6][7][8][9][10][11] Thanks to the generation of knock-out mice, the physiological and pathophysiological roles of the NCX2 and NCX3 isoforms in the brain have been elucidated. 4,5,12 In contrast, studies investigating the role of NCX1 in stroke have been hampered by difficulties met in developing a global NCX1 knock-out mice due to its embryonic lethality.…”

Section: Introductionmentioning

confidence: 99%

Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt

Molinaro

Sirabella²,

Pignataro

et al. 2016

J Cereb Blood Flow Metab

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Three different Na þ /Ca 2þ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are expressed in brain where they play a relevant role in maintaining Na þ and Ca 2þ homeostasis. Although the neuroprotective roles of NCX2 and NCX3 in stroke have been elucidated, the relevance of NCX1 is still unknown because of embryonic lethality of its knockingout, heart dysfunctions when it is overexpressed, and the lack of selectivity in currently available drugs. To overcome these limitations we generated two conditional genetically modified mice that upon tamoxifen administration showed a selective decrease or increase of NCX1 in cortical and hippocampal neurons. Interestingly, in cortex and hippocampus NCX1 overexpression increased, where NCX1 knock-out reduced, both exchanger activity and Akt1 phosphorylation, a neuronal survival signaling. More important, mice overexpressing NCX1 showed a reduced ischemic volume and an amelioration of focal and general deficits when subjected to transient middle cerebral artery occlusion. Conversely, NCX1-knock-out mice displayed a worsening of brain damage, focal and neurological deficits with a decrease in Akt phosphorylation. These results support the idea that NCX1 overexpression/activation may represent a feasible therapeutic opportunity in stroke intervention.

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A New Concept: A 1-42 Generates a Hyperfunctional Proteolytic NCX3 Fragment That Delays Caspase-12 Activation and Neuronal Death

Cited by 67 publications

References 53 publications

Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning

Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning

Involvement of the Na+/Ca2+ exchanger isoform 1 (NCX1) in Neuronal Growth Factor (NGF)-induced Neuronal Differentiation through Ca2+-dependent Akt Phosphorylation

Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt

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