Effects of Na+-Ca2+ exchanger activity on the α-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate-induced Ca2+ influx in cerebellar Purkinje neurons

Kim, Y.T.; Park, Y.J.; Jung, Sang-Yong; Seo, Wha Sook; Suh, Chang Kook

doi:10.1016/j.neuroscience.2004.11.045

Cited by 13 publications

(12 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In Purkinje cerebellar neurons, NCX also contributes to Ca 2 þ transients upon activation of AMPA receptors, although the consequences for cell viability were not addressed. 33 Here we show, for the first time, that in conditions of selective activation of AMPA receptors, NCX contributes not only to initial Ca 2 þ influx but also to a delayed increase in intracellular Ca 2 þ , following the AMPA receptor activation in hippocampal neurons. This increase is not as dramatic as the canonical delayed Ca 2 þ deregulation but, nevertheless, a significant population of cells present a sustained increased in [Ca 2 þ ] i 30-40 min after the stimulation with KA plus CTZ.…”

Section: Discussionmentioning

confidence: 61%

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

et al. 2007

View full text Add to dashboard Cite

Proteolytic cleavage of the Na þ /Ca 2 þ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca 2 þ dynamics, calpain activation and cell viability, in a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. The sodium-calcium exchanger (NCX) plays a fundamental role in controlling Na þ and Ca 2 þ homeostasis. 1,2 NCX primarily extrudes Ca 2 þ in exchange for Na þ , whereas upon neuronal depolarization, Na þ is pumped out by NCX, while Ca 2 þ is pumped in. In pathophysiological conditions, overactivation of glutamate receptors can cause the reversal of NCX, leading to Ca 2 þ entry into the cell. 3 Three NCX genes have been identified, NCX1, 4 NCX2 5 and NCX3. 6 In excitotoxic cell death, an increase in intracellular free calcium concentration ([Ca 2 þ ] i ) may directly cause activation of Ca 2 þ -dependent cysteine proteases, the calpains. Calpains modulate a variety of physiological processes, 7 and are important mediators of cell death. 8,9 Calpains mediate the neurotoxic effect of N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons by a caspase-independent cell death mechanism of excitotoxicity. 10 Calpains are also involved in the neurotoxic effect caused by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in cultured hippocampal neurons, 11 and in hippocampal slice cultures. 12 During excitotoxic neurodegeneration, calpains are responsible for the proteolysis of several cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters. 13 Recently, the involvement of calpains in the cleavage of NCX was described in cultured cerebellar granule neurons exposed to glutamate and following brain ischemia. 14 The NCX3 subtype is inactivated by proteolytic cleavage by calpains, and is no longer able to pump Ca 2 þ out of the cell, thus enhancing cell death. Furthermore, NCX3 was shown to be more relevant for cell survival than NCX1 or NCX2, namely in cultured cerebellar granule neurons. 14, 15 We recently reported that neurotoxicity induced by activation of AMPA receptors is characterized by calpain activation, lack of caspase activation, nuclear condensation/fragmentation, release of cytochrome c from mitochondria, decreased intracellular ATP levels, production of nitric oxide, moderate superoxide production and increased levels of peroxynitrite. [16][17][18] In this in vitro model of excitotoxicity, the cell

show abstract

Section: Discussionmentioning

confidence: 61%

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

et al. 2007

View full text Add to dashboard Cite

show abstract

“…However, it was evident that KB-R7943 caused some side effects, such as the inhibition of SOCI, depression of high K + -induced increase in [Ca 2+ ]i, Nakamura et al, 2000;Pintado et al, 2000). In this study, AS technique was employed to suppress the NCX activity in osteoblasts, as used in other cells (Slodzinski et al, 1995;Slodzinski and Blaustein, 1998;Kim et al, 2005). Pretreatments of osteoblasts with AS suppressed the expression of NCX protein, as shown in Figure 1.…”

Section: Discussionmentioning

confidence: 85%

“…The ASdependent suppression of NCX protein was also supported by measurements of the changes in intracellular Ca 2+ changes ( Figure 2). As described previously, the physiological activity of NCX was evaluated by measuring Na + -dependent Ca 2+ influx employing an experimental design that allows the NCX to operate in reverse mode (Park et al, 2001;Kim et al, 2005). The Na + -dependent Ca 2+ influx via the reverse mode of NCX was reduced significantly by AS-pretreatment.…”

Section: Discussionmentioning

confidence: 99%

Na+-Ca2+ exchanger modulates Ca2+ content in intracellular Ca2+ stores in rat osteoblasts

Jung

Park²,

Park³

et al. 2007

Exp Mol Med

View full text Add to dashboard Cite

Abstract]i. In AS-pretreated cells, the expression and activity of alkaline phosphatase (ALP), an osteogenic marker, were decreased. However, the cell viability was not affected by AS-pretreatment. Suppression of NCX activity by the AS-pretreatment decreased ATP-activated Ca 2+ release from intracellular stores and significantly enhanced Ca 2+ influx via store operated calcium influx (SOCI), compared to those of S-pretreated or control cells. These results strongly suggest that NCX has a regulatory role in cellular Ca 2+ pathways in osteoblasts by modulating intracellular Ca 2+ content.

show abstract

“…entry via the reverse NCX. Earlier it was shown that AMPA-induced DCD in Purkinje cells [19], in primary hippocampal neurons [24], and in cerebellar granule neurons [37,46] was predominantly caused by Ca 2? influx via the reverse NCX but not through the ion channel of the AMPA/KA receptors.…”

Section: Discussionmentioning

confidence: 99%

“…KB-R7943 was also shown to protect against irreversible elevation of [Ca 2? ] i evoked by anoxia, brain trauma or excitotoxicity in cultured neurons and astrocytes [13,[15][16][17][18][19][20][21][22]. In ischemic spinal cord white matter, KB-R7943 protected dorsal column slices against OGD even when removal of external Ca 2?…”

mentioning

confidence: 99%

Neuroprotective Effect of KB-R7943 Against Glutamate Excitotoxicity is Related to Mild Mitochondrial Depolarization

Storozhevykh¹,

Senilova²,

Brustovetsky

et al. 2009

Neurochem Res

View full text Add to dashboard Cite

KB-R7943, an inhibitor of a reversed Na(+)/Ca(2+) exchanger, exhibits neuroprotection against glutamate excitotoxicity. Taking into consideration that prolonged exposure of neurons to glutamate induces delayed calcium deregulation (DCD) and irreversible decrease of mitochondrial membrane potential (Deltapsi(mit)), we examined the effect of KB-R7943 on glutamate and kainate-induced [Ca(2+)](i) and on Deltapsi(mit) changes in rat cultured cerebellar granule neurons. 15 micromol/l KB-R7943 significantly delayed the onset of DCD in response to kainate but not in response to glutamate. In spite of [Ca(2+)](i) overload, KB-R7943 considerably improved the [Ca(2+)](i) recovery and restoration of Deltapsi(mit) after glutamate and kainate washout and increased cell viability after glutamate exposure. In resting neurons, KB-R7943 induced a statistically significant decrease in Deltapsi(mit). KB-R7943 also depolarized isolated brain mitochondria and slightly inhibited mitochondrial Ca(2+) uptake. These findings suggest that mild mitochondrial depolarization and diminution of Ca(2+) accumulation in the organelles might contribute to neuroprotective effect of KB-R7943.

show abstract

Effects of Na+-Ca2+ exchanger activity on the α-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate-induced Ca2+ influx in cerebellar Purkinje neurons

Cited by 13 publications

References 46 publications

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Na+-Ca2+ exchanger modulates Ca2+ content in intracellular Ca2+ stores in rat osteoblasts

Neuroprotective Effect of KB-R7943 Against Glutamate Excitotoxicity is Related to Mild Mitochondrial Depolarization

Contact Info

Product

Resources

About