The Role of Glia in Stress

Skatchkov, Serguei N.; Woodbury-Fariña, Michel A.; Eaton, Misty J.

doi:10.1016/j.psc.2014.08.008

Cited by 45 publications

(47 citation statements)

References 292 publications

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“…Altered brain polyamine metabolism may impact AD progression through several mechanisms, including modulation of cholinergic neurotransmission and activity of NMDA receptors [67]. While high polyamine concentrations have been shown to reduce neuronal survival, they provide trophic support during synaptogenesis in the developing brain and are therefore likely to play complex, pleiotropic roles in AD progression [68][69][70].…”

Section: Polyamine Synthesis and Catabolism (Fig 6)mentioning

confidence: 99%

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

et al. 2020

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Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's

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Section: Polyamine Synthesis and Catabolism (Fig 6)mentioning

confidence: 99%

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

et al. 2020

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“…Polyamines (PAs) are involved in numerous physiological processes including gene expression, protein and nucleic acid function and synthesis, protection against oxidative stress 1 , 2 , and increasing longevity 3 – 5 . The brain contains large amounts of PAs, mainly spermidine and spermine 6 – 8 , and an age-dependent depletion of PAs has been reported 4 , 5 , 9 . Trauma also causes release and loss of PAs in the brain 6 .…”

Section: Introductionmentioning

confidence: 99%

“…Astrocytes rather than neurons contain spermidine and spermine in the cortex and hippocampus 7 , as well as in Müller and Bergmann glial cells in the retina 11 , 12 and cerebellum 7 , respectively. This suggests that PAs are transported into the glia from external sources through blood and cerebrospinal fluid 1 , 2 , 8 to be further diffused through the glial network 8 , 13 . PAs can regulate glial 8 , 12 – 16 and other cell receptors/channels 17 , 18 and transporters 14 , 15 intracellularly and extracellularly.…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that PAs are transported into the glia from external sources through blood and cerebrospinal fluid 1 , 2 , 8 to be further diffused through the glial network 8 , 13 . PAs can regulate glial 8 , 12 – 16 and other cell receptors/channels 17 , 18 and transporters 14 , 15 intracellularly and extracellularly.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular spermine prevents acid-induced uncoupling of Cx43 gap junction channels

Skatchkov

Bukauskas

Benedikt³

et al. 2015

NeuroReport

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Polyamines (PAs), such as spermine and spermidine, modulate the activity of numerous receptors and channels in the central nervous system (CNS) and are stored in glial cells; however, little attention has been paid to their role in the regulation of connexin (Cx)-based gap junction channels. We have previously shown that PAs facilitate diffusion of Lucifer Yellow through astrocytic gap junctions in acute brain slices; therefore, we hypothesized that spermine can regulate Cx43-mediated (as the most abundant Cx in astrocytes) gap junctional communication. We used electrophysiological patch-clamp recording from paired Novikoff cells endogenously expressing Cx43 and HeLaCx43-EGFP transfectants to study pH-dependent modulation of cell–cell coupling in the presence or absence of PAs. Our results showed (i) a higher increase in gap junctional communication at higher concentrations of cytoplasmic spermine, and (ii) that spermine prevented uncoupling of gap junctions at low intracellular pH. Taken together, we conclude that spermine enhances Cx43-mediated gap junctional communication and may preserve neuronal excitability during ischemia and trauma when pH in the brain acidifies. We, therefore, suggest a new role of spermine in the regulation of a Cx43-based network under (patho)physiological conditions.

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“…Inward rectification of Kir4.1-containing channels is caused by voltage-dependent block of the channel pore by intracellular Mg 2ϩ and polyamines such as SPM (45 Table 1.…”

Section: Resultsmentioning

confidence: 99%

Novel KCNJ10 Gene Variations Compromise Function of Inwardly Rectifying Potassium Channel 4.1

Méndez-González¹,

Kucheryavykh²,

Zayas‐Santiago

et al. 2016

Journal of Biological Chemistry

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The KCNJ10 gene encoding Kir4.1 contains numerous SNPs whose molecular effects remain unknown. We investigated the functional consequences of uncharacterized SNPs (Q212R, L166Q, and G83V) on homomeric (Kir4.1) and heteromeric (Kir4.1-Kir5.1) channel function. We compared these with previously characterized EAST/SeSAME mutants (G77R and A167V) in kidney-derived tsA201 cells and in glial cell-derived C6 glioma cells. The membrane potentials of tsA201 cells expressing G77R and G83V were significantly depolarized as compared with WTKir4.1, whereas cells expressing Q212R, L166Q, and A167V were less affected. Furthermore, macroscopic currents from cells expressing WTKir4.1 and Q212R channels did not differ, whereas currents from cells expressing L166Q, G83V, G77R, and A167V were reduced. Unexpectedly, L166Q current responses were rescued when co-expressed with Kir5.1. In addition, we observed notable differences in channel activity between C6 glioma cells and tsA201 cells expressing L166Q and A167V, suggesting that there are underlying differences between cell lines in terms of Kir4.1 protein synthesis, stability, or expression at the surface. Finally, we determined spermine (SPM) sensitivity of these uncharacterized SNPs and found that Q212R-containing channels displayed reduced block by 1 M SPM. At 100 M SPM, the block was equal to or greater than WT, suggesting that the greater driving force of SPM allowed achievement of steady state. In contrast, L166Q-Kir5.1 channels achieved a higher block than WT, suggesting a more stable interaction of SPM in the deep pore cavity. Overall, our data suggest that G83V, L166Q, and Q212R residues play a pivotal role in controlling Kir4.1 channel function.Inwardly rectifying potassium (Kir) 3 channels are involved in maintenance of negative resting membrane potential (1-3), potassium buffering (1, 4), extracellular glutamate clearance (1, 4, 5), myelination (6), and cell volume regulation (3, 7). Kir4.1 channels are tetramers formed by Kir4.1 (KCNJ10) subunits. Kir4.1-containing channels are expressed in glial cells (8 -14) including in astrocytic end feet surrounding blood vessels (9, 15-17) and surrounding neuronal synapses (9, 17) where they are involved in maintenance of extracellular [K ϩ ] o and glutamate homeostasis (4,11,18). These functions are critical as inability to control [K ϩ ] o and glutamate alters neuronal excitability and may lead to seizures and neuronal death (4, 18 -20). Similarly in the retina, Kir4.1-dependent Kir channels are involved in homeostasis of extracellular potassium produced by neuronal activity in a process called potassium siphoning (9, 14, 21, 22).Kir4.1 subunits are also prominently expressed in the distal convoluted tubules in the kidneys (23) where they are involved in K ϩ recycling (24) and in the ear, specifically in the stria vascularis, where they are responsible for producing the endocochlear potential (7). Complete absence or loss-of-function mutations in these channel subunits cause EAST/SeSAME syndrome characterized by seizures, se...

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The Role of Glia in Stress

Cited by 45 publications

References 292 publications

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

Intracellular spermine prevents acid-induced uncoupling of Cx43 gap junction channels

Novel KCNJ10 Gene Variations Compromise Function of Inwardly Rectifying Potassium Channel 4.1

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