Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

Stridh, Malin H.; Tranberg, Mattias; Weber, Stephen G.; Blomstrand, Fredrik; Sandberg, Mats

doi:10.1074/jbc.m704153200

Cited by 62 publications

(56 citation statements)

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“…Although separated cultures allow us to dissect in detail the A␤ 25-35 -induced hemichannel activity in individual cellular types, the use of acute hippocampal slices was essential to study this response in a more integrated system. Up to now, the presence of functional hemichannels in brain slices (Liu et al, 2006;Rouach et al, 2008;Stridh et al, 2008) was solely observed under extracellular Ca 2ϩ /Mg 2ϩ -free condition, a protocol that promotes hemichannel opening but does not reflect a physiological situation. Here, we show that A␤ [25][26][27][28][29][30][31][32][33][34][35] induces hemichannel activity in hippocampal microglia, astrocytes, and neurons under normal extracellular divalent cationic conditions.…”

Section: A␤-induced Neuronal Death Occurs Through a Sequence Of Hemicmentioning

confidence: 99%

Amyloid β-Induced Death in Neurons Involves Glial and Neuronal Hemichannels

et al. 2011

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The mechanisms involved in Alzheimer's disease are not completely understood and how glial cells contribute to this neurodegenerative disease remains to be elucidated. Because inflammatory treatments and products released from activated microglia increase glial hemichannel activity, we investigated whether amyloid-␤ peptide (A␤) could regulate these channels in glial cells and affect neuronal viability. Microglia, astrocytes, or neuronal cultures as well as acute hippocampal slices made from GFAP-eGFP transgenic mice were treated with the active fragment of A␤. Hemichannel activity was monitored by single-channel recordings and by time-lapse ethidium uptake, whereas neuronal death was assessed by Fluoro-Jade C staining. We report that low concentrations of A␤ 25-35 increased hemichannel activity in all three cell types and microglia initiate these effects triggered by A␤. Finally, neuronal damage occurs by activation of neuronal hemichannels induced by ATP and glutamate released from A␤ 25-35 -activated glia. These responses were observed in the presence of external calcium and were differently inhibited by hemichannel blockers, whereas the A␤ 25-35 -induced neuronal damage was importantly reduced in acute slices made from Cx43 knock-out mice. Thus, A␤ leads to a cascade of hemichannel activation in which microglia promote the release of glutamate and ATP through glial (microglia and astrocytes) hemichannels that induces neuronal death by triggering hemichannels in neurons. Consequently, this work opens novel avenues for alternative treatments that target glial cells and neurons to maintain neuronal survival in the presence of A␤.

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Section: A␤-induced Neuronal Death Occurs Through a Sequence Of Hemicmentioning

confidence: 99%

Amyloid β-Induced Death in Neurons Involves Glial and Neuronal Hemichannels

et al. 2011

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“…4). Connexins and glutamate/aspartate transporters (GLAST) have also been suggested to mediate the efflux of GSH in excitable cells (87,204,224,225) (Table 1 and Fig. 4).…”

Section: Fig 4 Plasma Membrane Gsh Efflux Pumps Distinct Candidatementioning

confidence: 99%

Glutathione Efflux and Cell Death

Franco

Cidlowski

2012

Antioxidants & Redox Signaling

200

128

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Significance: Glutathione (GSH) depletion is a central signaling event that regulates the activation of cell death pathways. GSH depletion is often taken as a marker of oxidative stress and thus, as a consequence of its antioxidant properties scavenging reactive species of both oxygen and nitrogen (ROS/RNS). Recent Advances: There is increasing evidence demonstrating that GSH loss is an active phenomenon regulating the redox signaling events modulating cell death activation and progression. Critical Issues: In this work, we review the role of GSH depletion by its efflux, as an important event regulating alterations in the cellular redox balance during cell death independent from oxidative stress and ROS/RNS formation. We discuss the mechanisms involved in GSH efflux during cell death progression and the redox signaling events by which GSH depletion regulates the activation of the cell death machinery. Future Directions: The evidence summarized here clearly places GSH transport as a central mechanism mediating redox signaling during cell death progression. Future studies should be directed toward identifying the molecular identity of GSH transporters mediating GSH extrusion during cell death, and addressing the lack of sensitive approaches to quantify GSH efflux.

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“…13,[15][16][17][18] In this manner, Cx hemichannels could have an influence on the progression of the cell death process as has been documented in HeLa cells transfected with Cx43 exposed to various apoptotic agents 15 and to trigger apoptosis in Marshall and L2 lung epithelial cells in response to oxidative cell stress. 6 In addition, they are the essential transducers of the antiapoptotic effects of bisphosphonates, drugs used in the treatment of bone diseases, and may thus promote cell survival as well.…”

mentioning

confidence: 99%

“…They have been shown to release molecules such as adenosine triphosphate (ATP), glutamate, nicotinamide adenine dinucleotide (NAD þ ), prostaglandins and glutathione. 5,11,16,18,20 These substances may act in a paracrine manner on surrounding cells thereby modulating the spatial spreading of the cell death process. 17 The aim of this study was to investigate the role of both Cx channels in the communication of apoptotic signals to surrounding cells.…”

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confidence: 99%