A novel inward‐rectifying K+ current with a cell‐cycle dependence governs the resting potential of mammalian neuroblastoma cells.

Arcangeli, Annarosa; Bianchi, Laura; Becchetti, Andrea; Faravelli, Laura; Coronnello, Marcella; Mini, Emanuele; Olivotto, Massimo; Wanke, Enzo

doi:10.1113/jphysiol.1995.sp021065

Cited by 224 publications

(281 citation statements)

References 35 publications

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“…Western blotting performed on both cell lines and on hERG1-transfected HEK 293 cells, for control, confirmed that only U138 cells expressed the hERG1 protein ( Figure 6B). The mean V rest of U138 cells was À18 mV, which is similar to the values reported for hERG1-expressing tumour cells (Arcangeli et al, 1995;Schönherr et al, 1999). Moreover, WAY induced a dose-dependent V rest depolarisation (Table 3) …”

Section: Herg Inhibition Reduces Vegf Secretion In Glioblastoma Celsupporting

confidence: 83%

“…An alternative approach to distinguish I IRK from I hERG or I hELK2 is application of 100 mM Cs þ or Ba 2 þ . Such concentrations are ineffective on hERG/hELK2 channels (Arcangeli et al, 1995;Becchetti et al, 2002), but strongly inhibit IRK. The latter procedure is particularly useful to isolate I IRK from I hELK2 , which is insensitive to WAY.…”

Section: Resultsmentioning

confidence: 99%

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hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

et al. 2005

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Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K þ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K þ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K þ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies.

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Section: Herg Inhibition Reduces Vegf Secretion In Glioblastoma Celsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

et al. 2005

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“…Previous studies have shown that cultured as well as hippocampal astrocytes display a wide range of RMPs, inconsistent with an exclusive role for K IR that predicts RMPs close to E K ; the biophysical properties of ERG, in contrast, predict a more positive resting potential (Arcangeli et al, 1995;Bianchi et al, 1998), as found in a large subpopulation of astrocytes D'Ambrosio et al, 1998). In the present study, we found variable levels of ERG-K IR coexpression, consistent with the variable resting potentials found across astrocytes.…”

Section: Discussionmentioning

confidence: 97%

Do Glia Have Heart? Expression and Functional Role forEther-A-Go-GoCurrents in Hippocampal Astrocytes

et al. 2000

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Potassium homeostasis plays an important role in the control of neuronal excitability, and diminished buffering of extracellular K results in neuronal Hyperexcitability and abnormal synchronization. Astrocytes are the cellular elements primarily involved in this process. Potassium uptake into astrocytes occurs, at least in part, through voltage-dependent channels, but the exact mechanisms involved are not fully understood. Although most glial recordings reveal expression of inward rectifier currents (K IR ), it is not clear how spatial buffering consisting of accumulation and release of potassium may be mediated by exclusively inward potassium fluxes. We hypothesized that a combination of inward and outward rectifiers cooperate in the process of spatial buffering. Given the pharmacological properties of potassium homeostasis (sensitivity to Cs ϩ ), members of the ether-a-go-go (ERG) channel family widely expressed in the nervous system could underlie part of the process. We used electrophysiological recordings and pharmacological manipulations to demonstrate the expression of ERG-type currents in cultured and in situ hippocampal astrocytes. Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarizationand depolarization-activated glial currents, and ERG blockade impaired clearance of extracellular potassium with little direct effect on hippocampal neuron excitability. Immunocytochemical analysis revealed ERG protein mostly confined to astrocytes; ERG immunoreactivity was absent in presynaptic and postsynaptic elements, but pronounced in glia surrounding the synaptic cleft. Oligodendroglia did not reveal ERG immunoreactivity. Intense immunoreactivity was also found in perivascular astrocytic end feet at the blood-brain barrier. cDNA amplification showed that cortical astrocytes selectively express HERG1, but not HERG2-3 genes. This study provides insight into a possible physiological role of hippocampal ERG channels and links activation of ERG to control of potassium homeostasis.

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“…For example, proliferating human leukemia cells generally lack expression of K IR currents, but currents are upregulated rapidly on induction to differentiate into macrophages (Wieland et al, 1990). Mouse embryos (Day et al, 1993), HeLa cells (Takahashi et al, 1994), and neuroblastoma cells (Arcangeli et al, 1995) all exhibit a downregulation of K IR currents on entrance into S-phase of cell cycle. These studies and ours suggest that differentiated, postmitotic cells express K IR channels as their major channel type, whereas proliferating cells show upregulation of K D and a loss of K IR .…”

Section: Electrophysiological Changes In Gliosis Mirror Those Associamentioning

confidence: 99%

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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A novel inward‐rectifying K+ current with a cell‐cycle dependence governs the resting potential of mammalian neuroblastoma cells.

Cited by 224 publications

References 35 publications

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

Do Glia Have Heart? Expression and Functional Role forEther-A-Go-GoCurrents in Hippocampal Astrocytes

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

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