C5b-9-activated, Kv1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation

Tegla, Cosmin; Cudrici, Cornelia; Rózycka, M; Soloviova, Katerina; Ito, Takahiro; Singh, Anil; Khan, Aamer; Azimzadeh, Philippe; Andrian-Albescu, Maria; Khan, Ahmed; Niculescu, Florin; Rus, Violeta; Judge, Susan I.V.; Rus, Horea

doi:10.1016/j.yexmp.2011.04.006

Cited by 23 publications

(23 citation statements)

References 44 publications

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“…The involvement of Kv1.3 in controlling the proliferation of adult neural precursor cells (NPC) remains controversial. Although some authors could not confirm the pharmacological expression of Kv1.3 in adult NPC, others identified gene and protein expression in adult rat mesencephalic-derived neurospheres, NPCs and oligodendrocyte progenitor cells (OPCs) [43, 45–47]. We found Kv1.3 in both the SVZ in vivo and in NSCs derived from the SVZ.…”

Section: Discussionmentioning

confidence: 52%

Unconventional EGF-induced ERK1/2-mediated Kv1.3 endocytosis

Martínez-Mármol

Comes

Styrczewska

et al. 2015

Cell. Mol. Life Sci.

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The potassium channel Kv1.3 plays roles in immunity, neuronal development and sensory discrimination. Regulation of Kv1.3 by kinase signaling has been studied. In this context, EGF binds to specific receptors (EGFR) and triggers tyrosine kinase-dependent signaling, which down-regulates Kv1.3 currents. We show that Kv1.3 undergoes EGF-dependent endocytosis. This EGF-mediated mechanism is relevant because is involved in adult neural stem cell fate determination. We demonstrated that changes in Kv1.3 subcellular distribution upon EGFR activation were due to Kv1.3 clathrin-dependent endocytosis, which targets the Kv1.3 channels to the lysosomal degradative pathway. Interestingly, our results further revealed that relevant tyrosines and other interacting motifs, such as PDZ and SH3 domains, were not involved in the EGF-dependent Kv1.3 internalization. However, a new, and yet undescribed mechanism, of ERK1/2-mediated threonine phosphorylation is crucial for the EGF-mediated Kv1.3 endocytosis. Our results demonstrate that EGF triggers the down-regulation of Kv1.3 activity and its expression at the cell surface, which is important for the development and migration of adult neural progenitors.

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Section: Discussionmentioning

confidence: 52%

Unconventional EGF-induced ERK1/2-mediated Kv1.3 endocytosis

Martínez-Mármol

Comes

Styrczewska

et al. 2015

Cell. Mol. Life Sci.

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“…For example, the synaptic signal from neurons may influence the potassium channels of NG2 cells during the cell cycle and/or via the control of other intracellular signal cascades [89]. Previous studies have shown that voltage-gated potassium channels (Kv1.3) are important for controlling the complement C5b-9-induced cell cycle activation, both in vitro and in vivo [90]. The complement C5b-9 can induce the increased expression of Kv1.3 channels and the subsequent activation of the ERK1 and PI3K/Akt pathways, thereby contributing to the survival of NG2 cells.…”

Section: Neuron-ng2 Cell Synapses In Cnsmentioning

confidence: 99%

Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

Yang

Xiong

Yao

2013

BioMed Research International

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NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

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“…A decrease of K V 1.3 expression or outward K + current in Ols is essential for synthesis of myelin structural proteins and suppression of outward K + current promotes Ol maturation and survival. These results suggest a role of K V 1.3 in the regulation of Ol functionality (Chittajallu et al, 2002; Tegla et al, 2011). Moreover, activation of p53 has been detected in the Ol lineage cells in the postmortem brains of HAND patients, but not in control brains (Jayadev et al, 2007), suggesting Ols undergo apoptosis in HIV-1-infected brains.…”

Section: Introductionmentioning

confidence: 73%

“…It is also worth pointing out that, in addition to its toxic effect to mature Ols and myelin sheaths, Tat may also induce disturbance of myelin maintenance via K V 1.3 channels, such as Ol progenitor cells proliferation and differentiation, leading to myelin/white matter abnormalities as seen in the brains of HIV-1-infected patients. As basal activity of K V channels controls Ol proliferation and differentiation (Liu et al, 2015; Tegla et al, 2011; Vautier et al, 2004), the alteration of K V 1.3 channel activity by Tat may possibly disturb Ol lineage cell proliferation and differentiation, and ultimately myelin maintenance processes. In addition, K V 1.3 was shown to play a crucial role in controlling cell cycle activation (Tegla et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…As basal activity of K V channels controls Ol proliferation and differentiation (Liu et al, 2015; Tegla et al, 2011; Vautier et al, 2004), the alteration of K V 1.3 channel activity by Tat may possibly disturb Ol lineage cell proliferation and differentiation, and ultimately myelin maintenance processes. In addition, K V 1.3 was shown to play a crucial role in controlling cell cycle activation (Tegla et al, 2011). This may explain why PAP-treated Ols in our studies exhibited higher cell viability (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

Liu

et al. 2017

Neurobiology of Disease

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Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K+ (KV) channels induces cell apoptosis and Ols predominantly express K+ channel KV1.3. It is our hypothesis that Tat injures Ols via activation of KV1.3. To test this hypothesis, we studied the involvement of KV1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell KV1.3 current recorded under voltage clamp configuration and confirmed by specific KV1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of KV1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of KV1.3 gene. The Tat-induced Ol injury was validated in cultured rat brain slices, particularly in corpus callosum and striatum, that incubation of the slices with Tat resulted in myelin damage and reduction of myelin basic protein which were also blocked by aforementioned KV1.3 antagonists. Further studies revealed that Tat interacts with KV1.3 as determined by protein pull-down of recombinant GST-Tat with KV1.3 expressed in rat brains and HEK293 cells. Such protein-protein interaction may alter channel protein phosphorylation, resultant channel activity and consequent Ol/myelin injury. Taken together, these results demonstrate an involvement of KV1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.

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C5b-9-activated, Kv1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation

Cited by 23 publications

References 44 publications

Unconventional EGF-induced ERK1/2-mediated Kv1.3 endocytosis

Unconventional EGF-induced ERK1/2-mediated Kv1.3 endocytosis

Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

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