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Researching glutamate - induced cytotoxicity in different cell lines: a comparative/collective analysis/study.

Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD - Front Cell Neurosci (2015)

Bottom Line: Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione's reducing potential.However, in the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative.Different cell lines differ in their responses when exposed to glutamate.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Physiology, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki Greece.

ABSTRACT
Although glutamate is one of the most important excitatory neurotransmitters of the central nervous system, its excessive extracellular concentration leads to uncontrolled continuous depolarization of neurons, a toxic process called, excitotoxicity. In excitotoxicity glutamate triggers the rise of intracellular Ca(2+) levels, followed by up regulation of nNOS, dysfunction of mitochondria, ROS production, ER stress, and release of lysosomal enzymes. Excessive calcium concentration is the key mediator of glutamate toxicity through over activation of ionotropic and metabotropic receptors. In addition, glutamate accumulation can also inhibit cystine (CySS) uptake by reversing the action of the CySS/glutamate antiporter. Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione's reducing potential. Various cell lines have been employed in the pursuit to understand the mechanism(s) by which excitotoxicity affects the cells leading them ultimately to their demise. In some cell lines glutamate toxicity is exerted mainly through over activation of NMDA, AMPA, or kainate receptors whereas in other cell lines lacking such receptors, the toxicity is due to glutamate induced oxidative stress. However, in the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative. Different cell lines differ in their responses when exposed to glutamate. In this review article the responses of PC12, SH-SY5Y, HT-22, NT-2, OLCs, C6, primary rat cortical neurons, RGC-5, and SCN2.2 cell systems are systematically collected and analyzed.

No MeSH data available.


Related in: MedlinePlus

(A) Excitotoxicity mediated cell death: glutamate excitotoxicity causes Ca2+ mediated NO production leading to mitochondrial dysfunction resulting in superoxide production. Peroxynitrite is produced causing lipid peroxidation, direct DNA damage, and protein dysfunction. Peroxynitrite inhibits the mitochondrial electron transport chain, cytochrome c normal activity as well as of superoxide dismutase via protein nitration. Activation of ryanodine receptors in conjunction with accumulation of misfolded proteins and depletion of endoplasmic Ca2+ storage, results in ER dysfunction (ER-stress). These facts can provoke caspase mediated cell death and an eventual apoptotic cell death. Alternatively augmented intracellular Ca2+ concentration can lead to calpain activation engaging both calpain dependent and cathepsin dependent cell death. (B) mGluRs and NMDAR crosstalk: both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism in a PKC or calmodulin depended manner.
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Figure 3: (A) Excitotoxicity mediated cell death: glutamate excitotoxicity causes Ca2+ mediated NO production leading to mitochondrial dysfunction resulting in superoxide production. Peroxynitrite is produced causing lipid peroxidation, direct DNA damage, and protein dysfunction. Peroxynitrite inhibits the mitochondrial electron transport chain, cytochrome c normal activity as well as of superoxide dismutase via protein nitration. Activation of ryanodine receptors in conjunction with accumulation of misfolded proteins and depletion of endoplasmic Ca2+ storage, results in ER dysfunction (ER-stress). These facts can provoke caspase mediated cell death and an eventual apoptotic cell death. Alternatively augmented intracellular Ca2+ concentration can lead to calpain activation engaging both calpain dependent and cathepsin dependent cell death. (B) mGluRs and NMDAR crosstalk: both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism in a PKC or calmodulin depended manner.

Mentions: Both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism. Alternatively others (Minakami et al., 1997; Ishikawa et al., 1999; Shinohara et al., 2001) support that both mGluR1 and mGluR5 can interact with calmodulin in a calcium dependent manner, proposing that other molecules besides PKC may be responsible for the mGluR1 mediated activation of Pyk2/Src and the potentiation NMDARs currents (Figure 3). Group II (mGluR2 and 3) and III (mGluR4, 6, 7, and 8) are coupled to Gi/G0 proteins leading to inhibition of adenylate cyclase decreasing the levels of cAMP in the cytoplasm (Conn and Pin, 1997). Subunits of metabotropic receptors (groups I, II, and III) are also expressed in microglia. Groups II and III through the suppression of intracellular cAMP levels inhibit the export of potential neurotoxic glutamate from microglia offering a neuroprotective role (McMullan et al., 2012).


Researching glutamate - induced cytotoxicity in different cell lines: a comparative/collective analysis/study.

Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD - Front Cell Neurosci (2015)

(A) Excitotoxicity mediated cell death: glutamate excitotoxicity causes Ca2+ mediated NO production leading to mitochondrial dysfunction resulting in superoxide production. Peroxynitrite is produced causing lipid peroxidation, direct DNA damage, and protein dysfunction. Peroxynitrite inhibits the mitochondrial electron transport chain, cytochrome c normal activity as well as of superoxide dismutase via protein nitration. Activation of ryanodine receptors in conjunction with accumulation of misfolded proteins and depletion of endoplasmic Ca2+ storage, results in ER dysfunction (ER-stress). These facts can provoke caspase mediated cell death and an eventual apoptotic cell death. Alternatively augmented intracellular Ca2+ concentration can lead to calpain activation engaging both calpain dependent and cathepsin dependent cell death. (B) mGluRs and NMDAR crosstalk: both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism in a PKC or calmodulin depended manner.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362409&req=5

Figure 3: (A) Excitotoxicity mediated cell death: glutamate excitotoxicity causes Ca2+ mediated NO production leading to mitochondrial dysfunction resulting in superoxide production. Peroxynitrite is produced causing lipid peroxidation, direct DNA damage, and protein dysfunction. Peroxynitrite inhibits the mitochondrial electron transport chain, cytochrome c normal activity as well as of superoxide dismutase via protein nitration. Activation of ryanodine receptors in conjunction with accumulation of misfolded proteins and depletion of endoplasmic Ca2+ storage, results in ER dysfunction (ER-stress). These facts can provoke caspase mediated cell death and an eventual apoptotic cell death. Alternatively augmented intracellular Ca2+ concentration can lead to calpain activation engaging both calpain dependent and cathepsin dependent cell death. (B) mGluRs and NMDAR crosstalk: both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism in a PKC or calmodulin depended manner.
Mentions: Both mGluR1 and mGluR5 lead to the potentiation of NMDA receptor currents via Src-dependent mechanism. Alternatively others (Minakami et al., 1997; Ishikawa et al., 1999; Shinohara et al., 2001) support that both mGluR1 and mGluR5 can interact with calmodulin in a calcium dependent manner, proposing that other molecules besides PKC may be responsible for the mGluR1 mediated activation of Pyk2/Src and the potentiation NMDARs currents (Figure 3). Group II (mGluR2 and 3) and III (mGluR4, 6, 7, and 8) are coupled to Gi/G0 proteins leading to inhibition of adenylate cyclase decreasing the levels of cAMP in the cytoplasm (Conn and Pin, 1997). Subunits of metabotropic receptors (groups I, II, and III) are also expressed in microglia. Groups II and III through the suppression of intracellular cAMP levels inhibit the export of potential neurotoxic glutamate from microglia offering a neuroprotective role (McMullan et al., 2012).

Bottom Line: Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione's reducing potential.However, in the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative.Different cell lines differ in their responses when exposed to glutamate.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Physiology, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki Greece.

ABSTRACT
Although glutamate is one of the most important excitatory neurotransmitters of the central nervous system, its excessive extracellular concentration leads to uncontrolled continuous depolarization of neurons, a toxic process called, excitotoxicity. In excitotoxicity glutamate triggers the rise of intracellular Ca(2+) levels, followed by up regulation of nNOS, dysfunction of mitochondria, ROS production, ER stress, and release of lysosomal enzymes. Excessive calcium concentration is the key mediator of glutamate toxicity through over activation of ionotropic and metabotropic receptors. In addition, glutamate accumulation can also inhibit cystine (CySS) uptake by reversing the action of the CySS/glutamate antiporter. Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione's reducing potential. Various cell lines have been employed in the pursuit to understand the mechanism(s) by which excitotoxicity affects the cells leading them ultimately to their demise. In some cell lines glutamate toxicity is exerted mainly through over activation of NMDA, AMPA, or kainate receptors whereas in other cell lines lacking such receptors, the toxicity is due to glutamate induced oxidative stress. However, in the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative. Different cell lines differ in their responses when exposed to glutamate. In this review article the responses of PC12, SH-SY5Y, HT-22, NT-2, OLCs, C6, primary rat cortical neurons, RGC-5, and SCN2.2 cell systems are systematically collected and analyzed.

No MeSH data available.


Related in: MedlinePlus