Calcium-Binding Proteins Protect GABAergic Neurons of the Hippocampus from Hypoxia and Ischemia in vitro

Turovsky, Egor A.; Зинченко, В. П.; Gaidin, Sergei G.; Turovskaya, M. V.

doi:10.1134/s1990747818010105

Cited by 12 publications

(15 citation statements)

References 66 publications

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“…We showed in recent reports that elevation of [Ca 2+ ] i during brief episodes of hypoxia/reoxygenation occurs exclusively in GABAergic neurons. In addition, the percentage of necrotic cells 24 h after preconditioning is similar to that of GABAergic neurons in cell cultures [ 6 , 11 , 20 ]. It should be noted that mixed hippocampal cultures contain different cell types, including glutamatergic neurons, GABAergic neurons, and glial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Episodes of ischemia that last [ 2 min can lead to the death of neurons [4], especially GABAergic neurons without Ca 2? -binding proteins [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Acute episodes of hypoxia depress synaptic activity, while prolonged exposure to hypoxia leads to the death of neurons [ 3 ]. Episodes of ischemia that last > 2 min can lead to the death of neurons [ 4 ], especially GABAergic neurons without Ca 2+ -binding proteins [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

et al. 2020

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Hypoxia causes depression of synaptic plasticity, hyperexcitation of neuronal networks, and the death of specific populations of neurons. However, brief episodes of hypoxia can promote the adaptation of cells. Hypoxic preconditioning is well manifested in glutamatergic neurons, while this adaptive mechanism is virtually suppressed in GABAergic neurons. Here, we show that brain-derived neurotrophic factor (BDNF) overexpression in neurons enhances the preconditioning effect of brief episodes of hypoxia. The amplitudes of the NMDAR-and AMPARmediated Ca 2? responses of glutamatergic and GABAergic neurons gradually decreased after repetitive brief hypoxia/ reoxygenation cycles in cell cultures transduced with the (AAV)-Syn-BDNF-EGFP virus construct. In contrast, the amplitudes of the responses of GABAergic neurons increased in non-transduced cultures after preconditioning. The decrease of the amplitudes in GABAergic neurons indicated the activation of mechanisms of hypoxic preconditioning. Preconditioning suppressed apoptotic or necrotic cell death. This effect was most pronounced in cultures with BDNF overexpression. Knockdown of BDNF abolished the effect of preconditioning and promoted the death of GABAergic neurons. Moreover, the expression of the anti-apoptotic genes Stat3, Socs3, and Bcl-xl substantially increased 24 h after hypoxic episodes in the transduced cultures compared to controls. The expression of genes encoding the pro-inflammatory cytokines IL-10 and IL-6 also increased. In turn, the expression of pro-apoptotic (Bax, Casp-3, and Fas) and proinflammatory (IL-1b and TNFa) genes decreased after hypoxic episodes in cultures with BDNF overexpression. Inhibition of vesicular BDNF release abolished its protective action targeting inhibition of the oxygen-glucose deprivation (OGD)-induced [Ca 2? ] i increase in GABAergic and glutamatergic neurons, thus promoting their death. Bafilomycin A1, Brefeldin A, and tetanus toxin suppressed vesicular release (including BDNF) and shifted the gene expression profile towards excitotoxicity, inflammation, and apoptosis. These inhibitors of vesicular release abolished the protective effects of hypoxic preconditioning in glutamatergic neurons 24 h after hypoxia/reoxygenation cycles. This finding indicates a significant contribution of vesicular BDNF release to the development of the mechanisms of hypoxic preconditioning. Thus, our results demonstrate that BDNF plays a pivotal role in the activation and enhancement of the preconditioning effect of brief episodes of hypoxia and promotes tolerance of the most vulnerable populations of GABAergic neurons to hypoxia/ischemia.

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Section: Discussionmentioning

confidence: 99%

“…Episodes of ischemia that last [ 2 min can lead to the death of neurons [4], especially GABAergic neurons without Ca 2? -binding proteins [5,6].…”

Section: Introductionmentioning

confidence: 99%

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BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

et al. 2020

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“…This finding may suggest that neurons expressing CB are more sensitive and vulnerable to ER stress. In previous reports it was observed that Ca 2+ -binding proteins protect GABAergic neurons from an increase of Ca 2+ overload in various pathological states such as hypoxia and ischemia [35], amyotrophic lateral sclerosis [36] and glutamate toxicity [37], thus maintain Ca 2+ homeostasis. In different stress models, different subtypes of Ca 2+ -binding proteins stand out as protective of neurons.…”

Section: Inhibitor Intermediate Neurons Make Up Approximately 20-30% Of Cortical Neuronsmentioning

confidence: 99%

BDNF eksikliği ve endoplazmik retikulum stresinin GABAerjik sistem üzerindeki etkileri

Hacioglu¹,

Cırrık²,

Yüzüak³

et al. 2021

Pamukkale Medical Journal

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Protective pathways against endoplasmic reticulum stress in neurons are activated via brain-derived neurotrophic factor. However, it is not known how the inhibitory intermediate neuron types expressing the different Ca 2+ -binding proteins of GABAergic system will be affected with changes in Ca 2+ homeostasis, in conditions of chronic reduction of brain-derived neurotrophic factor and endoplasmic reticulum stress.The study was planned to reveal the interaction of these factors.Materials and methods: 6-8 months old (30-40 g), wild-type (WT) and brain-derived neurotrophic factor heterozygous (BDNF (+/-) ) male mice were used and 4 groups were formed. Groups 3 and 4 were treated with a single dose of tunicamycin to induce endoplasmic reticulum stress. On the 3rd day of tunicamycin injection, animals were sacrificed and blood and brain tissues were taken. In serum samples BDNF, in tissue homogenates GRP78, CHOP, Caspase-12, parvalbumin, calretinin, calbindin, GAD65 and GAD67 levels were investigated by ELISA method. One-way ANOVA and Tukey post-hoc tests were used for statistical evaluation.Results: Serum BDNF levels were significantly lower in BDNF (+/-) and tunicamycintreated BDNF (+/-) groups. Caspase-12 and CHOP levels significantly increased with tunicamycin injection. Calbindin level decreased significantly with endoplasmic reticulum stress. GAD65 and GAD67 levels were similar in WT and BDNF (+/-) groups. However, GAD65 level was significantly decreased during endoplasmic reticulum stress in WT and BDNF (+/-) groups. Conclusion:Endoplasmic reticulum stress caused a significant decrease in glutamic acid decarboxylase GAD65 isoform and caldindin levels. This result indicates that the sensitivity of varied intermediate neurons in GABAergic system to endoplasmic reticulum stress may be different.

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“…In addition to its role in insulin secretion it has been discussed whether secretagogin expressing neurons could be protected from pathological manifestations and cell death in diseases like AD. It has been shown, that CBPs like parvalbumin, calbindin-D 28K and calretinin (i.e., Ca 2+ buffers) protect neurons from detrimental Ca 2+ overload as it occurs for instance in ischemic conditions (Turovsky et al, 2018). Although secretagogin is considered to be mainly a Ca 2+ sensor, it also has one high-affinity Ca 2+ binding site and could also have some buffering capacity (Rogstam et al, 2007).…”

Section: Secretagogin In Disorders and Diseases Of The Cnsmentioning

confidence: 99%

20 Years of Secretagogin: Exocytosis and Beyond

Maj

Wagner

Tretter

2019

Front. Mol. Neurosci.

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Calcium is one of the most important signaling factors in mammalian cells. Specific temporal and spatial calcium signals underlie fundamental processes such as cell growth, development, circadian rhythms, neurotransmission, hormonal actions and apoptosis. In order to translate calcium signals into cellular processes a vast number of proteins bind this ion with affinities from the nanomolar to millimolar range. Using classical biochemical methods an impressing number of calcium binding proteins (CBPs) have been discovered since the late 1960s, some of which are expressed ubiquitously, others are more restricted to specific cell types. In the nervous system expression patterns of different CBPs have been used to discern different neuronal cell populations, especially before advanced methods like single-cell transcriptomics and activity recording were available to define neuronal identity. However, understanding CBPs and their interacting proteins is still of central interest. The post-genomic era has coined the term “calciomics,” to describe a whole new research field, that engages in the identification and characterization of CBPs and their interactome. Secretagogin is a CBP, that was discovered 20 years ago in the pancreas. Consecutively it was found also in other organs including the nervous system, with characteristic expression patterns mostly forming cell clusters. Its regional expression and subcellular location together with the identification of protein interaction partners implicated, that secretagogin has a central role in hormone secretion. Meanwhile, with the help of modern proteomics a large number of actual and putative interacting proteins has been identified, that allow to anticipate a much more complex role of secretagogin in developing and adult neuronal cells. Here, we review recent findings that appear like puzzle stones of a greater picture.

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Calcium-Binding Proteins Protect GABAergic Neurons of the Hippocampus from Hypoxia and Ischemia in vitro

Cited by 12 publications

References 66 publications

BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

BDNF eksikliği ve endoplazmik retikulum stresinin GABAerjik sistem üzerindeki etkileri

20 Years of Secretagogin: Exocytosis and Beyond

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