Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases

Castaldo, Pasqualina; Cataldi, Mauro; Magi, Simona; Lariccia, Vincenzo; Arcangeli, Sara; Amoroso, Salvatore

doi:10.1016/j.pneurobio.2008.09.017

Cited by 77 publications

(76 citation statements)

References 203 publications

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“…Indeed, the scientific community devoted to the research on neurodegenerative diseases has not paid attention to the mNCX until recently, due to its emerging role in the mitochondrial/cytosolic [Ca 2+ ] trafficking 29 and its implication in the development of neurological diseases. 30 Existence of a Na + /Ca 2+ exchange in mitochondria was first reported by Carafoli. 31 The further discovery of the benzothiazepine derivative CGP37157 as a mNCX blocker constituted a breakthrough for the functional characterization of the mNCX 32 ( Figure 1).…”

Section: + Concentrations ([Camentioning

confidence: 87%

“…39,45 More recently, the mNCX has been considered an interesting target to develop novel compounds for neuroprotection. 30 In this context, blockade of the mNCX by ITH12505 and CGP37157 could be a contributing factor in their protection effect. Thus, futile mitochondrial Ca 2+ cycling (mCC) causes energy dissipation, what is particularly active in neurons overstimulated by glutamate.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

González‐Lafuente

Egea

León

et al. 2012

ACS Chem. Neurosci.

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Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca 2+ handling, by its blocking effect of the mitochondria Na + /Ca 2+ exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2′ of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to CGP37157 in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3−30 μM, while CGP37157 only protected at 30 μM. Both compounds caused blockade of Ca 2+ channels in high K + -depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood−brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na + /Ca 2+ exchanger and L-type voltage-dependent Ca 2+ channels, having antioxidant properties.

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Section: + Concentrations ([Camentioning

confidence: 87%

Section: ■ Conclusionmentioning

confidence: 99%

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

González‐Lafuente

Egea

León

et al. 2012

ACS Chem. Neurosci.

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“…Cytosolic and mitochondrial Ca 2ϩ overloads are principal pathophysiological events during brain ischemia. The majority of studies suggest a neuroprotective role for blocking the mitochondrial exchanger activity (11). A harmful effect of mitochondrial Na ϩ /Ca 2ϩ exchange activity following ischemic-like conditions was shown in rat hippocampal slices, where a prolonged neuronal cytosolic Ca 2ϩ rise triggered by toxic levels of NMDA was augmented by elevation of cytosolic Na ϩ and blocked by CGP-37157 (87).…”

Section: Mitochondrial Na ؉ /Ca 2؉ Exchange In Brain and Secretory Symentioning

confidence: 99%

“…Here, we briefly describe several functional, molecular, kinetic, and regulatory aspects of the mitochondrial NCX, review its molecular identification, and discuss its physiological and pathophysiological roles. The interested reader is also referred to excellent reviews describing in more detail the physiological implications of mitochondrial Ca 2ϩ shuttling (8,9) and the role of the mitochondrial NCX (10,11).…”

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confidence: 99%

Molecular Identity and Functional Properties of the Mitochondrial Na+/Ca2+ Exchanger

Palty

Hershfinkel

Sekler

2012

Journal of Biological Chemistry

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The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca 2؉ shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca 2؉ signaling, and determines cell fate. Mitochondrial Ca 2؉ transport is mediated primarily by two major transporters: a Ca 2؉ uniporter that mediates Ca 2؉ uptake and a Na ؉ /Ca 2؉ exchanger that subsequently extrudes mitochondrial Ca 2؉ . In this minireview, we focus on the specific role of the mitochondrial Na ؉ /Ca 2؉ exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes.

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“…Mitochondrial NCX has been postulated to be present on the mitochondrial inner membrane 12,13) and to have functional properties different from those of plasmalemmal NCX, such as transport stoichiometry and ion selectivity, [14][15][16][17][18] but details still remain to be clarified. CGP-37157, a benzothiazepine compound, was reported to inhibit the mitochondrial NCX without affecting the L-type Ca 2+ channel, the Na + -K + -ATPase of the cardiac sarcolemma, or the Ca 2+ -ATPase of the cardiac sarcoplasmic reticulum at the concentration of 10 µM.…”

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confidence: 99%

Pharmacological Discrimination of Plasmalemmal and Mitochondrial Sodium–Calcium Exchanger in Cardiomyocyte-Derived H9c2 Cells

2015

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The Na + -Ca 2+ exchanger (NCX) is involved in the physiological and pathophysiological regulation of intracellular Ca 2+ concentration in various cell types including cardiomyocytes. Although the major role of plasmalemmal NCX in cardiomyocytes is to extrude Ca 2+ from the cell and maintain low cytoplasmic Ca 2+ concentration, 1) NCX is also considered to be responsible for the pathogenesis of ischemia-reperfusion and arrhythmia.2,3) Concerning pharmacological inhibition of NCX, SEA0400 {2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline}, a benzyloxyphenyl compound, was established as a potent inhibitor of NCX with minimum effects on other plasmalemmal ion channels and transporters. [4][5][6] In voltage-clamped guinea pig ventricular myocytes, 1 µM SEA0400, which inhibited the plasmalemmal NCX current by more than 80%, had no effect on the Na + current, L-type Ca 2+ current, delayed rectifier K + current, inwardly rectifying K + current.5) The involvement of plasmalemmal NCX in ouabaininduced arrhythmogenesis, 7) ischemia-reperfusion injury 8,9)

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Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases

Cited by 77 publications

References 203 publications

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

Molecular Identity and Functional Properties of the Mitochondrial Na+/Ca2+ Exchanger

Pharmacological Discrimination of Plasmalemmal and Mitochondrial Sodium–Calcium Exchanger in Cardiomyocyte-Derived H9c2 Cells

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