Cloning and Functional Expression of Rat eag2, a New Member of the Ether-à-go-go Family of Potassium Channels and Comparison of Its Distribution with That of eag1

Ludwig, Jost; Weseloh, Rüdiger; Karschin, Christine; Liu, Q.; Netzer, Rainer; Engeland, Birgit; Stansfeld, Catherine E.; Pongs, Olaf

doi:10.1006/mcne.2000.0851

Cited by 72 publications

(113 citation statements)

References 29 publications

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“…The overall pattern of eag1 and eag2 transcripts was similar to previously reported results using lower-resolution methods Ludwig et al, 2000). Eag1 expression was most prominent in the cerebral cortex, hippocampus, cerebellum, and olfactory bulb (Fig.…”

Section: Differential Expression Of Eag and Kcnq K ؉ Channel Transcrisupporting

confidence: 88%

“…However, the closing of different types of EAG channels can produce similar relaxations, albeit with different kinetics. Moreover, muscarinic agonists also inhibit eag and erg channels (Stansfeld et al, 1996;Selyanko et al, 1999;Ludwig et al, 2000), demanding more detailed kinetic and pharmacological experiments to identify the channels mediating M-like currents in specific neurons. The distributions reported in this study will be an important aid in this process.…”

Section: Discussionmentioning

confidence: 99%

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Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain

2001

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The members of the three subfamilies (eag, erg, and elk) of the ether-a-go-go (EAG) family of potassium channel pore-forming subunits express currents that, like the M-current (I M ), could have considerable influence on the subthreshold properties of neuronal membranes, and hence the control of excitability. A nonradioactive in situ hybridization (NR-ISH) study of the distribution of the transcripts encoding the eight known EAG family subunits in rat brain was performed to identify neuronal populations in which the physiological roles of EAG channels could be studied. These distributions were compared with those of the mRNAs encoding the components of the classical M-current (Kcnq2 and Kcnq3). NR-ISH was combined with immunohistochemistry to specific neuronal markers to help identify expressing neurons. The results show that each EAG subunit has a specific pattern of expression in rat brain. EAG and Kcnq transcripts are prominent in several types of excitatory neurons in the cortex and hippocampus; however, only one of these channel components (erg1) was consistently expressed in inhibitory interneurons in these areas. Some neuronal populations express more than one product of the same subfamily, suggesting that the subunits may form heteromeric channels in these neurons. Many neurons expressed multiple EAG family and Kcnq transcripts, such as CA1 pyramidal neurons, which contained Kcnq2, Kcnq3, eag1, erg1, erg3, elk2, and elk3. This indicates that the subthreshold current in many neurons may be complex, containing different components mediated by a number of channels with distinct properties and neuromodulatory responses.

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Section: Differential Expression Of Eag and Kcnq K ؉ Channel Transcrisupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain

2001

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“…We identified from the literature, the Allen Brain Atlas (14) and the CORTx browser (15), three robust markers of mouse neocortical layer 4 neurons: Eag2/Kcnh5, a potassium ion channel gene (16,17); Rorb/Nr1f2, a transcription factor gene (18); and Whrn/Dfnb31 (14), which encodes a cytoplasmic protein (Figs. S1 and S2).…”

Section: Molecular Evidence For a Neocortical Cell-type Homology Betweenmentioning

confidence: 99%

Cell-type homologies and the origins of the neocortex

Dugas-Ford

Rowell

Ragsdale

2012

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

256

314

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The six-layered neocortex is a uniquely mammalian structure with evolutionary origins that remain in dispute. One long-standing hypothesis, based on similarities in neuronal connectivity, proposes that homologs of the layer 4 input and layer 5 output neurons of neocortex are present in the avian forebrain, where they contribute to specific nuclei rather than to layers. We devised a molecular test of this hypothesis based on layer-specific gene expression that is shared across rodent and carnivore neocortex. Our findings establish that the layer 4 input and the layer 5 output cell types are conserved across the amniotes, but are organized into very different architectures, forming nuclei in birds, cortical areas in reptiles, and cortical layers in mammals.T he evolutionary origins of the mammalian neocortex have been the subject of debate for over a century (1-3). Although the six-layered neocortex is remarkably well conserved in all extant mammals, it is not present in our closest living relatives, the reptiles and birds. Birds in particular are an extremely successful radiation with large brains, but the bird dorsal telencephalon does not include a morphologically identifiable cortex; it is, instead, a collection of nuclei (4).Studies of the neurochemistry, anatomy, and physiology of the central region of the bird telencephalon, which is called the dorsal ventricular ridge (DVR), have shown conclusively that the DVR is a pallial structure (2). In mammals the pallium (dorsal telencephalon) includes the neocortex and the nuclei of the piriform lobe, specifically the claustrum and parts of the amygdala. A classical hypothesis that has attracted renewed interest from modern neuroembryologists and neuromorphologists proposes a field homology between the nuclei of the bird DVR and the mammalian piriform lobe nuclei, including the amygdala (5, 6). A second, more controversial hypothesis proposes that, despite the gross differences in morphology between bird DVR and mammalian neocortex, these structures share a homology (7-9).The best evidence for neocortex-DVR homology lies in their circuitries. Both the mammalian neocortex and avian DVR receive ascending sensory input from the thalamus, and both send outputs to brainstem premotor areas. These input and output territories form specific, well-defined populations of neurons in both mammals and birds. In mammals, layer 4 neocortical neurons receive thalamic input, and layer 5 neocortical neurons project to the brainstem. In birds there are separate DVR nuclei that receive projections from the thalamus or send axons to the brainstem. The most developed version of the neocortex-DVR hypothesis proposes homology between these input and output neurons at the cell-type level (7); specifically, that the layer 4 input (L4/I) and layer 5 output (L5/O) neurons of the neocortex share a common ancestry with neurons that populate the input and output nuclei of the DVR.These two prevailing hypotheses about DVR homology are in direct conflict; one is a field homology argument comparing...

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“…While its normal expression is largely confined to the CNS, EAG1 is highly expressed in >75% of human non-CNS cancers (Hemmerlein et al 2006;Mello de Queiroz et al 2006), although the mechanism by which EAG1 stimulates tumor growth is unknown. It is also unknown whether EAG2 (KCNH5, Kv10.2), which displays much higher expression in the cerebral cortex than the cerebellum (Ludwig et al 2000), has any involvement in cancer. To investigate the molecular mechanisms that drive MB development and progression, we conducted a genome-wide microarray analysis of mouse MBs and found that the expression of Eag2 was consistently up-regulated.…”

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confidence: 99%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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Cloning and Functional Expression of Rat eag2, a New Member of the Ether-à-go-go Family of Potassium Channels and Comparison of Its Distribution with That of eag1

Cited by 72 publications

References 29 publications

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain

Cell-type homologies and the origins of the neocortex

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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Cloning and Functional Expression of Rat eag2, a New Member of the Ether-à-go-go Family of Potassium Channels and Comparison of Its Distribution with That of eag1

Cited by 72 publications

References 29 publications

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K+Channels in Brain

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K+Channels in Brain

Cell-type homologies and the origins of the neocortex

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain

Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K⁺Channels in Brain