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

Secondo, Agnese; Esposito, Alba; Sirabella, Rossana; Boscia, Francesca; Pannaccione, Anna; Molinaro, Pasquale; Cantile, Monica; Ciccone, Roselia; Sisalli, Maria Josè; Scorziello, Antonella; Renzo, Gianfranco Di; Annunziato, Lucio

doi:10.1074/jbc.m114.555516

Cited by 27 publications

(27 citation statements)

References 39 publications

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“…6,[19][20][21] We hypothesized that NCX1 might play a relevant role in neuroprotection during brain ischemia since: (1) an increase in NCX1 expression/activity raises Akt phosphorylation, 22 a well-known signaling of neuronal survival [23][24][25] that increases neuronal resistance to brain ischemia; and (2) under anoxic conditions, NCX1 could work in the reverse mode, promoting Ca 2þ -influx and favoring Ca 2þ -refilling into the endoplasmic reticulum (ER), which is depleted under these conditions, thus allowing neurons to delay apoptosis. 21 To test this hypothesis and to overcome the genetic and pharmacological limitations, we used the wellknown Cre/loxP system to obtain two genetically modified mice, that, upon tamoxifen administration show an increase or decrease in NCX1 expression in the hippocampus and cortex, two brain regions involved in stroke.…”

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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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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“…KB-R7943, as an inhibitor of reverse-mode NCX1 activity, inhibits the influx of Ca 2+ into cells. A previous study demonstrated that NCX1 participates in neuronal differentiation through ionic regulation and Akt phosphorylation [27]. Here, KB-R7943 induced autophagosome accumulation by inhibiting mTOR kinase in a dose-dependent manner in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 66%

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux

et al. 2016

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We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 μM, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

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“…[37][38][39] The expression and function of NCX have been demonstrated in the cerebral neurons and neuroglia, in which they can function both in the Ca 2+ exit mode as well as Ca 2+ entry mode. [40][41][42][43] The latter induces neurotransmitter release as well as various signal transduction pathways. 44 However, little is known about the NCX in the myenteric neurons except for the observation made by Azuma et al that NCX1 and NCX2 are expressed in the myenteric neurons to regulate the motility of distal colon and gastric fundus by modulating ACh or NO release.…”

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Na⁺/Ca²⁺ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons

et al. 2018

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Aim: Our earlier studies showed that mechanical stretch activates inhibitory motor neurons of the oesophagus; however, the underlying molecular mechanisms are unclear. Here, we sought to examine if Na + /Ca 2+ exchanger 1 (NCX1) is responsible for the mechanosensitivity in the esophageal myenteric neurons (EMN) of rats and humans. Methods: The function of NCX1 in primary culture of neurons was determined using calcium imaging, and mechanosensitivity was tested using osmotic stretch and direct mechanical stretch. Axial stretch-induced relaxation of the lower esophageal sphincter (LES) was also studied in vivo in rats. Results: The expression and co-localization of NCX1 with nNOS were identified in the EMN from both rats and humans. The extracellular Ca 2+ entry caused by ATP through purinergic signalling in the rat EMN was significantly inhibited by selective NCX blockers. Removal of extracellular Na + to activate the Ca 2+ entry mode of NCX1 induced an increase in the cytoplasmic calcium ([Ca 2+ ] cyt ), which was attenuated by NCX blockers. Osmotic stretch and mechanical stretch-induced [Ca 2+ ] cyt signalling in the rat and human EMN were attenuated by NCX blockers as well as specific NCX1 knockdown. Osmotic stretch and mechanical stretch also induced [Ca 2+ ] cyt signalling in the Chinese hamster ovary (CHO) cells with NCX1 over-expression, which was attenuated by NCX blockers. Finally, NCX blockade inhibited axial stretch-activated LES relaxation in vivo experiments in the rats. Conclusions:We demonstrate a novel NCX1/Ca 2+ pathway in the mechanosensitive neurons of rat and human oesophagus, which may provide a potential therapeutic target for the treatment of oesophageal motility disorders. K E Y W O R D Sesophageal myenteric neurons, lower esophageal sphincter relaxation, mechanosensitive neurons, Na +/ Ca 2+ exchanger 1

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

Abstract: Background: NCX1 regulates intracellular Ca 2ϩ and Na ϩ homeostasis in neurons.

Cited by 27 publications

References 39 publications

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

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

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux

Na⁺/Ca²⁺ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons

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

Abstract: Background: NCX1 regulates intracellular Ca 2ϩ and Na ϩ homeostasis in neurons.

Cited by 27 publications

References 39 publications

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

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

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux

Na+/Ca2+ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons

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Na⁺/Ca²⁺ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons