Ion channel expression by white matter glia: The O-2A glial progenitor cell

Barres, Barbara A.; Koroshetz, Walter J.; Swartz, Kenton J.; Chun, Linda L. Y.; Corey, David P.

doi:10.1016/0896-6273(90)90109-s

Cited by 299 publications

(311 citation statements)

References 66 publications

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“…More detailed studies suggest that K ir channel expression correlates positively with cell differentiation, and K ir activity appears to be absent in proliferating glial cells. This relationship of K ir channel expression and cell differentiation has been demonstrated in astrocytes (MacFarlane and , Schwann cells (Wilson and Chiu, 1990;Konishi, 1994), Müller cells (Bringmann et al, 2000), and oligodendrocytes (Sontheimer et al, 1989;Barres et al, 1990) and thus appears to be a general feature of all glial cells. Intriguingly, changes in the expression and/or activity of K ir channels occur irrespective of how the change in differentiation state is initiated.…”

Section: Introductionmentioning

confidence: 58%

Mislocalization of K_ir channels in malignant glia

Olsen

Sontheimer

2004

Glia

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Inwardly rectifying potassium (K ir ) channels are a prominent feature of mature, postmitotic astrocytes. These channels are believed to set the resting membrane potential near the potassium equilibrium potential (E K ) and are implicated in potassium buffering. A number of previous studies suggest that K ir channel expression is indicative of cell differentiation. We therefore set out to examine K ir channel expression in malignant glia, which are incapable of differentiation. We used two established and widely used glioma cell lines, D54MG (a WHO grade 4 glioma) and STTG-1 (a WHO grade 3 glioma), and compared them to immature and differentiated astrocytes. Both glioma cell lines were characterized by large outward K + currents, depolarized resting membrane potentials (V m )(-38.5 ± 4.2 mV, D54 and -28.1 ± 3.5 mV, STTG1), and relatively high input resistances (R m ) (260.6 ± 64.7 MΩ, D54 and 687.2 ± 160.3 MΩ, STTG1). These features were reminiscent of immature astrocytes, which also displayed large outward K + currents, had a mean V m of -51.1 ± 3.7 and a mean R m value of 627.5 ± 164 MΩ. In contrast, mature astrocytes had a significantly more negative resting membrane potential (-75.2 ± 0.56 mV), and a mean R m of 25.4 ± 7.4 MΩ. Barium (Ba 2+ ) sensitive K ir currents were >20-fold larger in mature astrocytes (4.06 ± 1.1 nS/pF) than in glioma cells (0.169 ± 0.033 nS/pF D54, 0.244 ± 0.04 nS/pF STTG1), which had current densities closer to those of dividing, immature astrocytes (0.474 ± 0.12 nS/pF). Surprisingly, Western blot analysis shows expression of several K ir channel subunits in glioma cells (K ir 2.3, 3.1, and 4.1). However, while in astrocytes these channels localize diffusely throughout the cell, in glioma cells they are found almost exclusively in either the cell nucleus (K ir 2.3 and 4.1) or ER/Golgi (3.1). These data suggest that mislocalization of K ir channel proteins to intracellular compartments is responsible for a lack of appreciable K ir currents in glioma cells.

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Section: Introductionmentioning

confidence: 58%

Mislocalization of K_ir channels in malignant glia

Olsen

Sontheimer

2004

Glia

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“…The expression of Na+ channels in glial cells in viva has been controversial, and it was unclear whether glial cells in viva express Na+ channels or whether these channels are an artifact of cell culture. However, recent patch-clamp recordings from acutely isolated rat optic nerve astrocytes (Barres et al, 1990) and identified glial cells in hippocampal brain slices (Sontheimer and Waxman, 1992a) have been able to demonstrate the expression of Na+ channels in astrocytes in situ, dismissing the notion that these channels are an artifact of cell culture. Ritchie and colleagues (Bevan et al, 1985) suggested that glial cells may synthesize Na+ channel destined to be donated to neurons and axons, thus reducing their metabolic load, and immunohistochemical studies showed that astrocyte end-feet in close proximity to nodes of Ranvier express Na+ channel immunoreactivity (Black et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Differential modulation of TTX-sensitive and TTX-resistant Na+ channels in spinal cord astrocytes following activation of protein kinase C

Thio

Sontheimer

1993

J. Neurosci.

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TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) Na+ currents are expressed in high densities (2–8 channels/microns2) in astrocytes cultured from neonatal rat spinal cord. The two Na+ current types differ up to 1000-fold in their TTX sensitivity and additionally have different steady-state activation (g-V) and inactivation (h infinity) curves. Expression of TTX-S and TTX-R Na+ currents is confined to morphologically distinguishable subtypes of astrocytes, allowing characterization of the two types of Na+ currents in isolation: stellate cells express TTX-S Na+ currents and flat pancake cells express TTX-R Na+ currents. Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) exhibited different effects on TTX-S and TTX-R Na+ currents. PMA reduced peak TTX-S Na+ currents by 25– 60%; in contrast, PMA potentiated peak TTX-R Na+ currents by 60–150%. These effects developed within minutes, and were typically not reversible. PMA effects were voltage dependent, and shifted steady- state Na+ current activation of TTX-R and TTX-S currents by 6 and 18 mV, respectively, but without affecting their steady-state current inactivation (h infinity). PMA treatment also changed Na+ current kinetics. TTX-R current activation (tau m) was faster and current inactivation (tau h) changed from a single- to a bi-exponential after PMA exposure, suggesting that PKC phosphorylation may have activated formerly quiescent Na+ channels. In contrast, TTX-S current activation (tau m) was unchanged, and current inactivation (tau h), on average, decreased by 50% following PMA exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…[5][6][7] The Na þ /Ca 2 þ exchanger (NCX), 8 a transmembrane domain protein, which, by operating in a bidirectional way, couples the efflux of Ca 2 þ to the influx of Na þ into the cell or, vice versa, the influx of Ca 2 þ to the efflux of Na þ , is involved in the regulation of diverse neuronal and glial cell functions. 8,9 Furthermore, NCX is involved in regulating intracellular Ca 2 þ concentration under pathological conditions and has been proposed as a potential therapeutic target in different disorders of the nervous system, including de-myelinating conditions such as MS, 10,11 ischemia-reperfusion injury, [12][13][14] and spinal cord injury.…”

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confidence: 99%

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

et al. 2011

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Changes in intracellular [Ca 2 þ ] i levels have been shown to influence developmental processes that accompany the transition of human oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes and are required for the initiation of the myelination and re-myelination processes. In the present study, we explored whether calcium signals mediated by the selective sodium calcium exchanger (NCX) family members NCX1, NCX2, and NCX3, play a role in oligodendrocyte maturation. Functional studies, as well as mRNA and protein expression analyses, revealed that NCX1 and NCX3, but not NCX2, were divergently modulated during OPC differentiation into oligodendrocyte phenotype. In fact, whereas NCX1 was downregulated, NCX3 was strongly upregulated during oligodendrocyte development. The importance of calcium signaling mediated by NCX3 during oligodendrocyte maturation was supported by several findings. Indeed, whereas knocking down the NCX3 isoform in OPCs prevented the upregulation of the myelin protein markers 2 0 ,3 0 -cyclic nucleotide-3 0 -phosphodiesterase (CNPase) and myelin basic protein (MBP), its overexpression induced an upregulation of CNPase and MBP. Furthermore, NCX3-knockout mice showed not only a reduced size of spinal cord but also marked hypo-myelination, as revealed by decrease in MBP expression and by an accompanying increase in OPC number. Collectively, our findings indicate that calcium signaling mediated by NCX3 has a crucial role in oligodendrocyte maturation and myelin formation. Oligodendrocytes, the myelin-forming cells of the CNS, arise from oligodendrocyte precursor cells (OPCs) that colonize both the gray and the white brain matter during development. 1 Although many OPCs differentiate into mature myelinating oligodendrocytes during the early and much later stages of human brain development, a considerable number of them do persist in the adult brain, and may provide a source of new oligodendrocytes, as well as protoplasmic astrocytes and neurons. 2,3 Because of their apparent stem-like characteristics, adult OPCs have recently gained much attention, for they are regarded as a potential reservoir of cells capable of self-renewal, differentiation, and re-myelination after CNS injury. 4 Thus, understanding how oligodendrocyte development proceeds and what factors govern the differentiation fate of OPCs is crucial to discover new effective therapeutic targets for de-myelinating diseases such as multiple sclerosis (MS).Changes in intracellular calcium levels have a critical role in OPC migration, lineage progression, and differentiation; furthermore, they are required for myelination and remyelination processes. [5][6][7] The Na þ /Ca 2 þ exchanger (NCX), 8 a transmembrane domain protein, which, by operating in a bidirectional way, couples the efflux of Ca 2 þ to the influx of Na þ into the cell or, vice versa, the influx of Ca 2 þ to the efflux of Na þ , is involved in the regulation of diverse neuronal and glial cell functions. 8,9 Furthermore, NCX is involved in regulating int...

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Ion channel expression by white matter glia: The O-2A glial progenitor cell

Cited by 299 publications

References 66 publications

Mislocalization of K_ir channels in malignant glia

Mislocalization of K_ir channels in malignant glia

Differential modulation of TTX-sensitive and TTX-resistant Na+ channels in spinal cord astrocytes following activation of protein kinase C

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

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Ion channel expression by white matter glia: The O-2A glial progenitor cell

Cited by 299 publications

References 66 publications

Mislocalization of Kir channels in malignant glia

Mislocalization of Kir channels in malignant glia

Differential modulation of TTX-sensitive and TTX-resistant Na+ channels in spinal cord astrocytes following activation of protein kinase C

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

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Mislocalization of K_ir channels in malignant glia

Mislocalization of K_ir channels in malignant glia