GluN2A-NMDA receptor–mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death

Deep, Satya Narayan; Mitra, Sumonto; Rajagopal, Sathyanarayanan; Paul, Surojit; Poddar, Ranjana

doi:10.1074/jbc.ra119.008820

Cited by 38 publications

(28 citation statements)

References 66 publications

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“…Interestingly, GluN2A signaling has been associated with cell survival through activation of the transcription factor CREB, leaving the mechanism of GluN2A-mediated potentiation to be somewhat perplexing in the context of potentiation from DNRAbs 62 . However, there is increasing evidence to suggest that GluN2A over-activation can contribute to excitotoxicity [62][63][64] . GluN2A contributes to both the acute and chronic phases of SLE neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

et al. 2020

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Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

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Section: Discussionmentioning

confidence: 99%

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

et al. 2020

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“…Whereas NMDARs containing GluN2A/C or D subunits did not reveal desensitization during the HCY activation [12,13], currents through GluN1/GluN2B NMDARs brie y declined to about 15 % of the peak amplitude because of the desensitization [12]. This observation exhibits why NMDARs containing GluN2A subunits, but not the GluN2B ones, mostly contribute to HCY-induced excitotoxicity in cortical neurons [12][13][14][15][16]. Cerebellar neurons expressing NMDARs containing GluN2C or 2D are also sensitive to the excitotoxic action of HCY since these receptors do not reveal desensitization during the HCY activation [13].…”

Section: Introductionmentioning

confidence: 84%

“…It is widely accepted that Glu [16,18,19,45] and HCY [7,8] induced neurodegeneration is caused by the permanent plasma membrane depolarization and cytosolic Ca 2+ overload of neurons, which is the condition known as excitotoxic stress [for review 45]. Under the excitotoxic stress, the maintenance of ionic gradients on the plasma membrane by NKA consumes ATP and burdens mitochondria, which, as a consequence, is followed by the loss of mitochondrial inner membrane voltage.…”

Section: Discussionmentioning

confidence: 99%

“…The latter ones are widely expressed in extrasynaptic regions of the plasma membrane, and it is thought to provide a major contribution to neurodegeneration [19]. Since rat cortical neurons express GluN2A and GluN2B [for review 48], the HCY effects are likely determined preferentially by the activation of GluN2A-containing NMDARs [12,16,20]. In contrast, Glu also activates GluN2B-containing NMDARs producing more Ca 2+ to be accumulated in the cytoplasm and pronounced drop of the mitochondrial inner membrane potential, which is usually associated with mitochondrial swelling and neuronal cell death [49].…”

Section: Necrosis At Short-term Excitotoxic Stressmentioning

confidence: 99%

“…The inhibition of PKA or PKC blocked ouabain induced neuroprotection against HCY, but not against Glu neurotoxicity. This observation can be related to the NMDAR subtype selectivity of HCY because GluN2A, but not GluN2B NMDAR subunits, mostly contribute to HCY toxicity in cortical neurons [12,[14][15][16] [17][18][19], while HCY causes sustained p38 MAPK activity [14]. As a result, p38 MAPK inhibition can protect neurons from short-term, but not long-term activation of NMDARs [62].…”

Section: Apoptosis At Long-term Excitotoxic Stressmentioning

confidence: 99%

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Calcium export from neurons and multi-kinase signaling cascades contribute to ouabain neuroprotection in hyperhomocysteinemia

Ivanova

Kokorina

Timofeeva

et al. 2020

Preprint

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Background: Subnanomolar ouabain binding to the Na,K-ATPase triggers intracellular signaling, prevents an overload of neurons with Ca2+, and their apoptosis caused by glutamate receptor agonists. Elevated plasma homocysteine (HCY), known as hyperhomocysteinemia, represents a risk factor for stroke and can exacerbate many neuronal disorders. HCY acts as a persistent N-methyl-D-aspartate receptor (NMDAR) agonist, which, in contrast to glutamate, desensitizes NMDARs containing GluN2B subunits. Mechanisms of HCY neurotoxicity remain not clearly understood since GluN2B-containing NMDARs provide a major contribution to excitotoxicity among glutamate receptors.Methods: Using fluorescent tools combined with the confocal microscopy, we compared 0.1 - 1 nM ouabain effects on the intracellular Ca2+ signaling, on the mitochondrial inner membrane voltage and the cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. We also studied an apoptosis-related protein expression and the involvement of some kinases in ouabain mediated effects.Results: In short insults HCY was less potent than glutamate as a neurotoxic agent. This amino acid induced the voltage loss (∆φmit) of 0.2 of the total mitochondrial inner membrane voltage (φmit) instead of ∆φmit = 0.7 for glutamate. We have found that subnanomolar ouabain exhibited rapid and postponed neuroprotective effects on neurons and (1) rapidly reduced the Ca2+ overload of neurons and the voltage loss of inner mitochondrial membranes evoked by glutamate and HCY, and (2) prevented neuronal apoptosis during 24 h treatments with glutamate or HCY. Using a set of specific kinase inhibitors such as PKA inhibitor, chelerythrine, and KN93, we demonstrated the role of multi-kinase signaling pathways involving PKC and PKA in neuronal survival caused by ouabain in hyperhomocysteinemia. Conclusions: Subnanomolar ouabain prevents neurodegeneration caused by glutamate and HCY. For both amino acids, ouabain evokes an acceleration of Ca2+ export by sodium-calcium exchangers from neurons preventing the voltage loss by mitochondrial inner membranes that rescue neurons in short insults. In prolonged insults, ouabain triggers intracellular neuroprotective cascades, including activation of PKA and PKC for HCY, but not for glutamate. This suggests that different appropriate pharmacology for hyperhomocysteinemia and glutamate excitotoxicity could be applied for clinical treatments.

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High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression

Field

Cracknell

Eastwood

et al. 2022

Human Psychopharmacology

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Objective Vitamins B6 and B12 are involved in metabolic processes that decrease neural excitation and increase inhibition. This double‐blind study investigated the effects of supplementation for 1 month with a high‐dose of B6 or B12, compared to placebo, on a range of behavioural outcome measures connected to the balance between neural inhibition and excitation. Methods 478 young adults were recruited over five linked phases. Self‐reported anxiety (N = 265) and depression (N = 146) were assessed at baseline and after supplementation. Several sensory measures acted as assays of inhibitory function and were assessed post‐supplementation only; these were surround suppression of visual contrast detection (N = 307), binocular rivalry reversal rate (N = 172), and a battery of tactile sensitivity tests (N = 180). Results Vitamin B6 supplementation reduced self‐reported anxiety and induced a trend towards reduced depression, as well as increased surround suppression of visual contrast detection, but did not reliably influence the other outcome measures. Vitamin B12 supplementation produced trends towards changes in anxiety and visual processing. Conclusions Our results suggest that high‐dose Vitamin B6 supplementation increases inhibitory GABAergic neural influences, which is consistent with its known role in the synthesis of GABA.

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GluN2A-NMDA receptor–mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death

Cited by 38 publications

References 66 publications

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

Calcium export from neurons and multi-kinase signaling cascades contribute to ouabain neuroprotection in hyperhomocysteinemia

High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression

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