K<sup>+</sup>Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

Knutson, Peter; Ghiani, Cristina A.; Zhou, Jiamin; Gallo, Vittorio; McBain, Chris J.

doi:10.1523/jneurosci.17-08-02669.1997

Cited by 145 publications

(166 citation statements)

References 57 publications

(84 reference statements)

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“…Similarly, glial progenitor cells are consistently 20 mV more depolarized than are oligodendrocytes or astrocytes (Sontheimer et al, 1989). A recent study showed that proliferation of O-2A cells could be inhibited by numerous depolarizing reagents, including conditions that increased intracellular Na ϩ (Knutson et al, 1997), suggesting that O-2A proliferation is controlled by changes in membrane potential. Yet, two studies in astrocytes (Pappas et al, 1994) and Schwann cells (Moor and Cole, 1963) showed antiproliferative effects of K ϩ channel blockers even in the absence of significant membrane depolarization.…”

Section: Electrophysiological Changes In Gliosis Mirror Those Associamentioning

confidence: 99%

“…Changes in [C a 2ϩ ] i have been associated with cell cycle progression in a number of cell types (Lewis and C ahalan, 1990;Means, 1994;Baran, 1996;Isfort et al, 1996). Surprisingly, however, studies investigating such a relationship in glial progenitor cells (Knutson et al, 1997) and astrocytes (Pappas et al, 1994) failed to show a conclusive dependence of cell cycle progression on changes in [C a 2ϩ ] i . Alterations in intracellular ions may induce gene expression, providing an attractive framework to explore f urther the interdependence among K ϩ channel expression, membrane depolarization, [Na ϩ ] i , [Ca 2ϩ ] i , and cell proliferation.…”

Section: Electrophysiological Changes In Gliosis Mirror Those Associamentioning

confidence: 99%

“…Thus in O2-A cells (Gallo et al, 1996), Schwann cells (Chiu and Wilson, 1989), retinal glial cells (Puro et al, 1989), and spinal cord astrocytes (Pappas et al, 1994), blockade of K ϩ channels retards proliferation. Underlying mechanisms are not well understood, but studies suggest that intracellular pH (Pappas et al, 1994) or intracellular Na ϩ (Knutson et al, 1997) are critically important. Moreover, involvement of ion channel activity in cell cycle control has been documented for other inexcitable cells (for review, see Sontheimer, 1995).…”

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Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

1997

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An in vitro injury model was used to examine the electrophysiological changes that accompany reactive gliosis. Mechanical scarring of confluent spinal cord astrocytes led to a threefold increase in the proliferation of scar-associated astrocytes, as judged by bromodeoxyuridine (BrdU) labeling. Whole-cell patch-clamp recordings demonstrated that current profiles differed absolutely between nonproliferating (BrdU Ϫ ) and proliferating (BrdU ϩ ) astrocytes. The predominant current type expressed in BrdU Ϫ cells was an inwardly rectifying K ϩ current (K IR ; 1.3 pS/pF). BrdU Ϫ cells also expressed transient outward K ϩ currents, accounting for less than one-third of total K ϩ conductance (G). In contrast, proliferating BrdU ϩ astrocytes exhibited a dramatic, approximately threefold reduction in K IR (0.45 pS/pF) but showed a twofold increase in the conductance of both transient (K A ) (0.67-1.32 pS/pF) and sustained (K D ) (0.42-1.10 pS/pF) outwardly rectifying K ϩ currents, with a G KIR : G KD ratio of 0.4. Relative expression of G KIR :G KD led to more negative resting potentials in nonproliferating (Ϫ60 mV) versus proliferating astrocytes (Ϫ53 mV; p ϭ 0.015). Although 45% of the nonproliferating astrocytes expressed Na ϩ currents (0.47 pS/pF), the majority of proliferating cells expressed prominent Na ϩ currents (0.94 pS/pF). Injury-induced electrophysiological changes are rapid and transient, appearing within 4 hr postinjury and, with the exception of K IR , returning to control conductances within 24 hr. These differences between proliferating and nonproliferating astrocytes are reminiscent of electrophysiological changes observed during gliogenesis, suggesting that astrocytes undergoing secondary, injury-induced proliferation recapitulate the properties of immature glial cells. The switch in predominance from K IR to K D appears to be essential for proliferation and scar repair, because both processes were inhibited by blockade of K D .

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Section: Electrophysiological Changes In Gliosis Mirror Those Associamentioning

confidence: 99%

Section: Electrophysiological Changes In Gliosis Mirror Those Associamentioning

confidence: 99%

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Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

1997

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“…A correlation exists between expression of the delayed, outward-rectifying voltage-gated K ϩ currents (I K ) and the proliferative potential of oligodendrocyte lineage cells (5)(6)(7)(8)(9). Proliferating OPs possess large I K , whereas postmitotic oligodendrocytes do not express such currents (5)(6)(7)(8)(9).…”

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Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Chittajallu

Chen

Wang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Proliferative oligodendrocyte progenitor cells (OPs) express large, delayed outward-rectifying K ؉ currents (IK), whereas nondividing immature and mature oligodendrocytes display much smaller I K. Here, we show that up-regulation of IK occurs in G1 phase of the cell cycle in purified cultured OPs and is the result of an RNA synthesis-dependent, selective increase of the K ؉ channel subunit proteins Kv1.3 and Kv1.5. In oligodendrocyte cells acutely isolated from developing rat brain, a decrease of cyclin D expression is observed as these cells mature along their lineage. This is accompanied by a decrease in Kv1.3 and Kv1.5 subunit expression, suggesting a role for these subunits in the proliferative potential of OPs in situ. IK expressed in OPs in subventricular zone and developing white matter in acutely isolated slice preparations were selectively blocked by antagonists of Kv1.3, illustrating the functional presence of this subunit in situ. Interestingly, Kv1.3 block inhibited S-phase entry of both purified OPs in culture and in tissue slice cultures. Thus, we employ both in vitro and in situ experimental approaches to show that (i) RNA-dependent synthesis of Kv1.3 and Kv1.5 subunit proteins occurs in G 1 phase of the OP cell cycle and is responsible for the observed increase in I K, and (ii) currents through Kv1.3-containing channels play a crucial role in G 1͞S transition of proliferating OPs. O ligodendrocytes, a major class of macroglia, are responsible for myelination in the central nervous system and primarily originate from highly proliferative oligodendrocyte precursor cells (OPs) in a spatially restricted central nervous system area termed the subventricular zone (SVZ; refs. 1 and 2). Under the influence of extrinsic trophic signals (3, 4), OPs migrate, proliferate, and the majority differentiate (by means of a number of intermediate cell stages) into myelinating oligodendrocytes.A correlation exists between expression of the delayed, outward-rectifying voltage-gated K ϩ currents (I K ) and the proliferative potential of oligodendrocyte lineage cells (5-9). Proliferating OPs possess large I K , whereas postmitotic oligodendrocytes do not express such currents (5-9). However, few studies have attempted to identify the cellular mechanisms responsible for these K ϩ channel changes in OPs. Furthermore, although the functional properties of these channels indicate that they are composed of subunits of the Kv1 subfamily (9, 10), the molecular identity of the K ϩ channel subunits involved in the developmental alterations of K ϩ channel expression in OPs has not been extensively analyzed.We have previously used a cell culture model system that allows OPs to be synchronized in a nonproliferative state (G 0 ) and be induced to enter the cell cycle upon mitogen treatment (11,12). By using this approach, we have previously shown that mitogen-induced entry of OPs into the cell cycle is accompanied by a marked increase in I K . § In the present study, we take further advantage of this culture system to: (i) analyze ...

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“…What could the function of this regenerative depolarization of OPCs be? The membrane depolarization and sodium influx mediated by the voltage-gated Na þ channels will raise the intracellular sodium concentration in the OPCs, which may block membrane K þ channels and inhibit OPC proliferation (Knutson et al, 1997). Regulation of proliferation could thus be different in the two classes of OPC which express, and which do not express, voltage-gated Na þ channels.…”

Section: S I G N a L P R O C E S S I N G B Y O P C Smentioning

confidence: 99%

Electrical signalling properties of oligodendrocyte precursor cells

2009

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yamina bakiri 1 , david attwell 1 and ragnhildur kara ' do ' ttir 2Oligodendrocyte precursor cells (OPCs) have become the focus of intense research, not only because they generate myelinforming oligodendrocytes in the normal CNS, but because they may be suitable for transplantation to treat disorders in which myelin does not form or is damaged, and because they have stem-cell-like properties in that they can generate astrocytes and neurons as well as oligodendrocytes. In this article we review the electrical signalling properties of OPCs, including the synaptic inputs they receive and their use of voltage-gated channels to generate action potentials, and we describe experiments attempting to detect output signalling from OPCs. We discuss controversy over the existence of different classes of OPC with different electrical signalling properties, and speculate on the lineage relationship and myelination potential of these different classes of OPC. Finally, we point out that, since OPCs are the main proliferating cell type in the mature brain, the discovery that they can develop into neurons raises the question of whether more neurons are generated in the mature brain from the classical sites of neurogenesis in the subventricular zone of the lateral ventricle and the hippocampal dentate gyrus or from the far more widely distributed OPCs.Keywords: Myelin, OPC, NG2, stem cell, neuron I N T R O D U C T I O NOligodendrocyte precursor cells (OPCs) transform into myelinating oligodendrocytes during development (Nishiyama et al., 2002), but are also present in the adult CNS where they comprise 5% of the cells and are the main proliferating cell type (Horner et al., 2000;Stallcup, 2002; Dawson et al., 2003). Damage to oligodendrocyte precursors, leading to reduced myelination, contributes to mental and physical impairment in periventricular leukomalacia (pre-or perinatal white matter injury leading to cerebral palsy; Volpe, 2001). Adult OPCs may form new myelinating oligodendrocytes in multiple sclerosis, and in brain or spinal cord injury (Levine, 1994;Gensert and Goldman, 1997;Keirstead et al., 1998;McTigue et al., 2001;Levine et al., 2001;Horner et al., 2002), and OPC transplants could serve as a basis for therapeutic remyelination (Windrem et al., 2008;Moreno-Manzano et al., 2009). This article will focus on the electrical signalling properties of OPCs which, as we will describe below, may play a crucial role in their development and their myelination of axons. D E F I N I N G O P C sIn the next section we will review several papers suggesting that OPCs are not a homogenous set of cells, but fall into at least two classes. To establish the range of properties of OPCs, it is essential to have criteria to define which cells are OPCs; so we will preface our review by examining the techniques available for doing this, and their advantages and pitfalls.Classically, OPCs have been defined antigenically, both in culture and in situ, by their expression of the proteoglycan NG2 (Nishiyama et al., 1996), the growth factor recept...

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K⁺Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

Cited by 145 publications

References 57 publications

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Electrical signalling properties of oligodendrocyte precursor cells

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K+Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

Cited by 145 publications

References 57 publications

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G 1 /S phase progression of the cell cycle

Electrical signalling properties of oligodendrocyte precursor cells

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K⁺Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle