High levels of synaptosomal Na+–Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease

Sokolow, Sophie; Luu, Sanh H.; Headley, Alison J.; Hanson, Alecia Y.; Kim, Taeree; Miller, Carol A.; Vinters, Harry V.; Gylys, Karen H.

doi:10.1016/j.ceca.2010.12.008

Cited by 39 publications

(38 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This cellular model is complementary to the BHK-cellular approach. Indeed, BHK-WT cells do not constitutively expressed any NCX isoform, BHK-NCX3 cells are genetic engineered cells to solely expressed NCX3-specific brain isoform whereas wild-type VMC neurons express NCX1, NCX2 and NCX3 isoforms (Canitano, 2002, Linck, 1998, Minelli, 2007, Nicoll, 1996, Sokolow, 2011). Due to the lack of selective NCX3 inhibitor, we opted to investigate the role of ziram induced DA toxicity in VMC neurons isolated from NCX3 knock-out mice (Molinaro, 2008, Molinaro, 2011, Pannaccione, 2012, Sokolow, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…Studies in NCX2 deficient mice implied that NCX2 is important for cognitive function (Jeon, 2003). We produced NCX3 knockout mice and showed that NCX3 plays a significant role in cognition (Molinaro et al, 2011), in oligodendrocyte differentiation (Boscia et al, 2013), in amyloid-beta pathology (Pannaccione et al, 2012, Sokolow et al, 2011) and is protective against ischemic damage (Cross et al, 2009, Jeffs et al, 2008, Molinaro et al, 2013, Molinaro et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

View full text Add to dashboard Cite

Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca2+) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca2+ dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca2+ homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium-calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK-WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca2+ concentration [Ca2+i] induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3−/−) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson’s disease and indicates new targets to slow down neuronal degeneration.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Three different isoforms of the NCX (NCX1, NCX2 and NCX3) have been characterized, cloned and detected in various tissues, including the central nervous system (Philipson and Nicoll, 1997; Quednau et al, 1997; Papa et al, 2003; Lytton, 2007). The NCX has been implicated in the pathophysiology of various neurological conditions, including Alzheimer’s disease (Bi et al, 2012; Sokolow et al, 2011), ischemia (Pignataro et al, 2004; Lee et al, 2005; Boscia et al, 2006), hypoxia (Secondo et al, 2007) and Parkinson’s disease (Ago et al, 2011). Although the role of the NCX in the pathogenesis of seizures and epilepsy remains poorly understood, we have reported that inhibition of Ca 2+ influx via NCX activity in the reverse mode reduced the incidence of pilocarpine-induced limbic seizures and status epilepticus (Martinez and N’Gouemo, 2010).…”

Section: Introductionmentioning

confidence: 99%

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

N’Gouemo¹

2013

Brain Research Bulletin

View full text Add to dashboard Cite

The Na+/Ca2+ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic-clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic-clonic components in 12–62% and 25–62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, 30 mg/kg; p.o.), clonic and tonic-clonic PTZ-induced generalized seizures were reduced in 25–50% and 38–63% of treated animals, respectively. SN-6 (0.3, 1, 3, mg/kg; p.o.) also significantly reduced PTZinduced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3, 30 mg/kg; p.o.) or SN-6 (3, 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic-clonic PTZ-induced seizures. These findings suggested that Ca2+ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic-clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.

show abstract

“…SLC8A1/NCX1 is widely expressed in most tissues although it is most abundant in the heart, while expression of SLC8A2/NCX2 is restricted to the brain and spinal cord and SLC8A3/NCX3 expression is restricted to the brain and skeletal muscle 74). The Na + /Ca 2+ exchanger is also expressed in immune cells, including SLC8A1/NCX1 and SLC8A3/NCX3 which are expressed in both macrophages and monocytes 75).…”

Section: Genetic Synergismmentioning

confidence: 99%

Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

Yeter¹,

Deth

Kuo

2013

Korean Circ J

View full text Add to dashboard Cite

Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca2+ release. Hg2+ sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca2+ from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca2+ release. Hg2+ increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg2+-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca2+. Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.

show abstract

High levels of synaptosomal Na+–Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease

Cited by 39 publications

References 51 publications

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

Contact Info

Product

Resources

About