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Ruolo dello scambiatore sodio-calcio nel danno neuronale indotto da policlorurati bifenili
No full textThe dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease
Full text linkGlutamate is the major excitatory neurotransmitter in the central nervous system. Beyond this function, glutamate also plays
a key role in intermediary metabolism in all organs and tissues, linking carbohydrate and amino acid metabolism via the
tricarboxylic acid cycle. Under both physiological and pathological conditions, we have recently found that the ability of
glutamate to fuel cell metabolism selectively relies on the activity of two main transporters: the sodium–calcium exchanger
(NCX) and the sodium-dependent excitatory amino-acid transporters (EAATs). In ischemic settings, when glutamate is
administered at the onset of the reoxygenation phase, the coordinate activity of EAAT and NCX allows glutamate to improve
cell viability by stimulating ATP production. So far, this phenomenon has been observed in both cardiac and neuronal models.
In this review, we focus on the most recent findings exploring the unusual activity of glutamate as a potential survival
factor in different settings
Cracking the code of sodium/calcium exchanger (NCX) gating: old and new complexities surfacing from the deep web of secondary regulations
No full textCell membranes spatially define gradients that drive the complexity of biological signals. To guarantee movements and exchanges of solutes between compartments, membrane transporters negotiate the passages of ions and other important molecules through lipid bilayers. The Na+/Ca2+ exchangers (NCXs) in particular play central roles in balancing Na+ and Ca2+ fluxes across diverse proteolipid borders in all eukaryotic cells, influencing cellular functions and fate by multiple means. To prevent progression from balance to disease, redundant regulatory mechanisms cooperate at multiple levels (transcriptional, translational, and post-translational) and guarantee that the activities of NCXs are finely-tuned to cell homeostatic requirements. When this regulatory network is disturbed by pathological forces, cells may approach the end of life. In this review, we will discuss the main findings, controversies and open questions about regulatory mechanisms that control NCX functions in health and disease
Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies
No full textAbstract Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described
Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: Detrimental role of Na+–Ca2+ exchanger
No full textSeveral molecular pathways involved in the development of cardiac hypertrophy are triggered by perturbation of intracellular Ca2+ homeostasis. Within the heart, Na+/Ca2+ exchanger 1 (NCX1) is one of the main determinant in controlling Ca2+ homeostasis. In cardiac hypertrophy and heart failure NCX1 expression and activity have been reported to be altered. It has been shown that chronic bacterial infections (sepsis, endocarditis, and myocarditis) can promote cardiac hypertrophy. Bacterial stressors, such as the Gram-negative endotoxin lipopolysaccharide (LPS), can directly or indirectly affect intracellular Ca2+ homeostasis in the heart and induce the development of cardiac hypertrophy. The present study aimed at evaluating the potential link between the signal pathways activated in LPS-exposed myocytes and NCX1. In the whole rat heart, LPS perfusion induced an early hypertrophy response during which NCX1 expression significantly increased. Notably, all these changes were completely prevented by the NCX inhibitor SN-6. We further dissect the role of NCX1 in the LPS-induced hypertrophic response in an in vitro cardiac model based on two H9c2 cardiomyoblast clones, namely H9c2-WT (lacking endogenous NCX1 expression) and H9c2-NCX1 (stably transfected with a functional NCX1). H9c2-NCX1 were more susceptible than H9c2-WT to develop a hypertrophic phenotype, and they displayed a significant increase in NCX1 expression and function after LPS treatment. SN-6 completely counteracted both hypertrophic response and exchanger alterations induced by LPS in H9c2-NCX1 cells, but it had no effects on H9c2-WT. Collectively, our results suggest that NCX1 plays a critical role in promoting myocardial hypertrophy triggered by LPS
Effects of ticagrelor on the sodium/calcium exchanger 1 (NCX1) in cardiac derived H9c2 cells
No full textTicagrelor is a direct acting and reversibly binding P2Y12 antagonist approved for the prevention of thromboembolic events. Clinical effects of ticagrelor cannot be simply accounted for by pure platelet inhibition, and off-target mechanisms can potentially play a role. In particular, recent evidence suggests that ticagrelor may also influence heart function and improve the evolution of myocardial ischemic injury by more direct effects on myocytes. The cardiac sodium/calcium exchanger 1 (NCX1) is a critical player in the generation and control of calcium (Ca2+) signals, which orchestrate multiple myocyte activities in health and disease. Altered expression and/or activity of NCX1 can have profound consequences for the function and fate of myocytes. Whether ticagrelor affects cardiac NCX1 has not been investigated yet. To explore this hypothesis, we analyzed the expression, localization and activity of NCX1 in the heart derived H9c2-NCX1 cells following ticagrelor exposure. We found that ticagrelor concentration- and time-dependently reduced the activity of the cardiac NCX1 in H9c2 cells. In particular, the inhibitory effect of ticagrelor on the Ca2+-influx mode of NCX1 was evident within 1 h and further developed after 24 h, when NCX1 activity was suppressed by about 55% in cells treated with 1 μM ticagrelor. Ticagrelor-induced inhibition of exchanger activity was reached at clinically relevant concentrations, without affecting the expression levels and subcellular distribution of NCX1. Collectively, these findings suggest that cardiac NCX1 is a new downstream target of ticagrelor, which may contribute to the therapeutic profile of ticagrelor in clinical practice
A new K+channel-independent mechanism is involved in the antioxidant effect of XE-991 in an in vitro model of glucose metabolism impairment: implications for Alzheimer’s disease
Full text linkAlzheimer's disease (AD) is a neurodegenerative disorder that represents the first cause of dementia. Although there has been significant progress in AD research, the actual mechanisms underlying this pathology remain largely unknown. There is increasing evidence that oxidative stress, metabolic alterations, and mitochondrial dysfunction are key players in the development and worsening of AD. As a result, in the past few years, remarkable attempts have been made to develop neuroprotective strategies against the impairment of mitochondrial dynamics and cell redox status. In the present study, we reveal a novel antioxidant K+ channel-independent effect of the M-current inhibitor XE-991 in SH-SY5Y cells differentiated with retinoic acid (RA) and primary rat cortical neurons exposed to the glycolysis inhibitor glyceraldehyde (GA). This experimental approach aimed to create a condition of hypometabolism accompanied by mitochondrial dysfunction and redox imbalance, as frequently observed in the beginning stage of the disease. We found that XE-991 exerted a neuroprotective action most likely through the resumption of superoxide dismutase (SOD) activity, which was significantly compromised during GA challenge. We also observed that the enhancement of SOD activity was accompanied by a sequence of positive effects; these included the reduction in basal Ca2+ levels within cytoplasmic and mitochondrial compartments, the decrease in mitochondrial reactive oxygen species (ROS) production, the modulation of AMPK/mTOR pathway, the recovery of ΔΨm collapse, the increase in the intracellular ATP content and the decrease in amyloid-β (Aβ) and hyperphosphorylated form of tau protein (pTau) levels. Collectively, our study reveals an off-target antioxidant effect of XE-991 and paves the way toward the further evaluation of new therapeutic uses of already existing molecules to accelerate the process of developing an effective therapy to counteract AD
Glutamate as a potential "survival factor" in an in vitro model of neuronal hypoxia/reoxygenation injury: Leading role of the Na + /Ca 2+ exchanger
Full text linkIn brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism,
culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and
reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R)
injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including
utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a
neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX)
and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the
role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/
reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant
cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset
of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP
levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited
such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with
small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these
proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate
in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these
findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings,
shedding a new light on the classical view of glutamate as detrimental factor
Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases.
No full textAbstract.
In neurons, as in other excitable cells, mitochondria extrude Ca(2+) ions from their matrix in exchange with cytosolic Na(+) ions. This exchange is mediated by a specific transporter located in the inner mitochondrial membrane, the mitochondrial Na(+)/Ca(2+) exchanger (NCX(mito)). The stoichiometry of NCX(mito)-operated Na(+)/Ca(2+) exchange has been the subject of a long controversy, but evidence of an electrogenic 3 Na(+)/1 Ca(2+) exchange is increasing. Although the molecular identity of NCX(mito) is still undetermined, data obtained in our laboratory suggest that besides the long-sought and as yet unfound mitochondrial-specific NCX, the three isoforms of plasmamembrane NCX can contribute to NCX(mito) in neurons and astrocytes. NCX(mito) has a role in controlling neuronal Ca(2+) homeostasis and neuronal bioenergetics. Indeed, by cycling the Ca(2+) ions captured by mitochondria back to the cytosol, NCX(mito) determines a shoulder in neuronal [Ca(2+)](c) responses to neurotransmitters and depolarizing stimuli which may then outlast stimulus duration. This persistent NCX(mito)-dependent Ca(2+) release has a role in post-tetanic potentiation, a form of short-term synaptic plasticity. By controlling [Ca(2+)](m) NCX(mito) regulates the activity of the Ca(2+)-sensitive enzymes pyruvate-, alpha-ketoglutarate- and isocitrate-dehydrogenases and affects the activity of the respiratory chain. Convincing experimental evidence suggests that supraphysiological activation of NCX(mito) contributes to neuronal cell death in the ischemic brain and, in epileptic neurons coping with seizure-induced ion overload, reduces the ability to reestablish normal ionic homeostasis. These data suggest that NCX(mito) could represent an important target for the development of new neurological drugs
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