Induced tolerance to glutamate neurotoxicity through down‐regulation of NR2 subunits of N‐methyl‐D‐aspartate receptors in cultured rat striatal neurons

Kambe, Yuki; Nakamichi, Noritaka; Takarada, Takeshi; Fukumori, Ryo; Yoneda, Yukio

doi:10.1002/jnr.22388

Cited by 12 publications

(4 citation statements)

References 52 publications

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“…Taken together with the downregulation of the NMDA receptor (NMDAR) subunit NR2B detected in the present study, our data suggest that HF diets would enhance Glu release (18).…”

Section: E399mentioning

confidence: 55%

High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission

Valladolid‐Acebes¹,

Merino²,

Principato³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

135

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Valladolid-Acebes I, Merino B, Principato A, Fole A, Barbas C, Lorenzo MP, García A, Del Olmo N, Ruiz-Gayo M, Cano V. High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission. Am J Physiol Endocrinol Metab 302: E396 -E402, 2012. First published November 22, 2011; doi:10.1152/ajpendo.00343.2011.-Obesity and high-fat (HF) diets have a deleterious impact on hippocampal function and lead to impaired synaptic plasticity and learning deficits. Because all of these processes need an adequate glutamatergic transmission, we have hypothesized that nutritional imbalance triggered by these diets might eventually concern glutamate (Glu) neural pathways within the hippocampus. Glu is withdrawn from excitatory synapses by specific uptake mechanisms involving neuronal (EAAT-3) and glial (GLT-1, GLAST) transporters, which regulate the time that synaptically released Glu remains in the extracellular space and, consequently, the duration and location of postsynaptic receptor activation. The goal of the present study was to evaluate in mouse hippocampus the effect of a short-term high-fat dietary treatment on 1) Glu uptake kinetics, 2) the density of Glu carriers and Glu-degrading enzymes, 3) the density of Glu receptor subunits, and 4) synaptic transmission and plasticity. Here, we show that HF diet triggers a 50% decrease of the Michaelis-Menten constant together with a 300% increase of the maximal velocity of the uptake process. Glial Glu carriers GLT-1 and GLAST were upregulated in HF mice (32 and 27%, respectively), whereas Glu-degrading enzymes glutamine synthase and GABA-decarboxilase appeared to be downregulated in these animals. In addition, HF diet hippocampus displayed diminished basal synaptic transmission and hindered NMDAinduced long-term depression (NMDA-LTD). This was coincident with a reduced density of the NR2B subunit of NMDA receptors. All of these results are compatible with the development of leptin resistance within the hippocampus. Our data show that HF diets upregulate mechanisms involved in Glu clearance and simultaneously impair Glu metabolism. Neurochemical changes occur concomitantly with impaired basal synaptic transmission and reduced NMDA-LTD. Taken together, our results suggest that HF diets trigger neurochemical changes, leading to a desensitization of NMDA receptors within the hippocampus, which might account for cognitive deficits. obesity; electrophysiology; learning; long-term depression; glutamate uptake; leptin resistance GLUTAMATE (Glu) uptake is a pivotal process regulating excitatory transmission within the central nervous system, and its efficacy accounts for the time that released Glu remains in the extracellular space and, consequently, the duration of postsynaptic receptor activation. Glu uptake is carried out by specific neuronal (EAAT-3) and glial (GLT-1, GLAST) transporters, which display dynamic processes aimed at improving Glu clearance under conditions leading to increased release of Glu (27, 34). Impairment of Glu uptake due to brain injury (24, 28...

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“…Taken together with the downregulation of the NMDA receptor (NMDAR) subunit NR2B detected in the present study, our data suggest that HF diets would enhance Glu release (18).…”

Section: E399mentioning

confidence: 55%

High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission

Valladolid‐Acebes¹,

Merino²,

Principato³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

135

View full text Add to dashboard Cite

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“…The efficacy of calpain-1 associated with NMDAR derives also from the fact that the protease is in proximity of its targets. The rapid calpain-1-mediated digestion of NR2B, which is known to be involved in the control of the Ca 2+ influx, could represent a possible defense mechanism against calcium overload [ 51 ]. We have demonstrated that the digestion of calpain targets at the NMDAR is mediated exclusively by resident calpain-1.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Calpain-1 and HSP90: New Insights into the Regulation of Localization and Activity of the Protease

et al. 2015

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Here we demonstrate that heat shock protein 90 (HSP90) interacts with calpain-1, but not with calpain-2, and forms a discrete complex in which the protease maintains its catalytic activity, although with a lower affinity for Ca2+. Equilibrium gel distribution experiments show that this complex is composed by an equal number of molecules of each protein partner. Moreover, in resting cells, cytosolic calpain-1 is completely associated with HSP90. Since calpain-1, in association with HSP90, retains its proteolytic activity, and the chaperone is displaced by calpastatin also in the absence of Ca2+, the catalytic cleft of the protease is not involved in this association. Thus, calpain-1 can form two distinct complexes depending on the availability of calpastatin in the cytosol. The occurrence of a complex between HSP90 and calpain-1, in which the protease is still activable, can prevent the complete inhibition of the protease even in the presence of high calpastatin levels. We also demonstrate that in basal cell conditions HSP90 and calpain-1, but not calpain-2, are inserted in the multi-protein N-Methyl-D-Aspartate receptor (NMDAR) complex. The amount of calpain-1 at the NMDAR cluster is not modified in conditions of increased [Ca2+]i, and this resident protease is involved in the processing of NMDAR components. Finally, the amount of calpain-1 associated with NMDAR cluster is independent from Ca2+-mediated translocation. Our findings show that HSP90 plays an important role in maintaining a given and proper amount of calpain-1 at the functional sites.

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“…A second issue concerns the fate of NMDAR after the digestion of NR2 subunits [ 9 , 29 ]. Furthermore, a number of studies have proposed that calpain-mediated degradation of NMDAR could act as an initial defense mechanism by reducing the number of functional NMDAR molecules, and consequently decreasing the extent of Ca 2+ influx [ 30 – 32 ]. More recently it has been reported that the activation of calpain 1 coupled with synaptic NMDAR can exert a role in neuroprotection, whereas the activation of calpain 2 coupled with extrasynaptic NMDAR is involved in neurodegeneration [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Physiological Roles of Calpain 1 Associated to Multiprotein NMDA Receptor Complex

et al. 2015

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We have recently demonstrated that in resting conditions calpain 1, but not calpain 2, is specifically associated to the N-Methyl-D-Aspartate receptor (NMDAR) multiprotein complex. We are here reporting that in SKNBE neuroblastoma cells or in freshly isolated nerve terminals from adult rat hippocampus, the proteolytic activity of calpain 1 resident at the NMDAR is very low under basal conditions and greatly increases following NMDAR stimulation. Since the protease resides at the NMDAR in saturating amounts, variations in Ca2+ influx promote an increase in calpain 1 activity without affecting the amount of the protease originally associated to NMDAR. In all the conditions examined, resident calpain 1 specifically cleaves NR2B at the C-terminal region, leading to its internalization together with NR1 subunit. While in basal conditions intracellular membranes include small amounts of NMDAR containing the calpain-digested NR2B, upon NMDAR stimulation nearly all the receptor molecules are internalized. We here propose that resident calpain 1 is involved in NMDAR turnover, and following an increase in Ca2+ influx, the activated protease, by promoting the removal of NMDAR from the plasma membranes, can decrease Ca2+ entrance through this channel. Due to the absence of calpastatin in such cluster, the activity of resident calpain 1 may be under the control of HSP90, whose levels are directly related to the activation of this protease. Observations of different HSP90/calpain 1 ratios in different ultrasynaptic compartments support this conclusion.

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Induced tolerance to glutamate neurotoxicity through down‐regulation of NR2 subunits of N‐methyl‐D‐aspartate receptors in cultured rat striatal neurons

Cited by 12 publications

References 52 publications

High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission

High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission

Interaction between Calpain-1 and HSP90: New Insights into the Regulation of Localization and Activity of the Protease

Physiological Roles of Calpain 1 Associated to Multiprotein NMDA Receptor Complex

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