Correlation between Kir4.1 expression and barium-sensitive currents in rat and human glioma cell lines

Madadi, Annett; Wolfart, Jakob; Lange, Falko; Brehme, Hannes; Linnebacher, Michael; Bräuer, Anja U.; Büttner, Andreas; Freiman, Thomas M.; Henker, Christian; Einsle, Anne; Rackow, Simone; Köhling, Rüdiger; Kirschstein, Timo; Müller, Susanne

doi:10.1016/j.neulet.2020.135481

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…As the electrophysiological features of GBM cells remain elusive, their role in neuron-cancer interactions is not fully understood. Using a human-based acute slice configuration, our study provides novel and robust evidence of neuron-like electrophysiological features of GBM cells at the leading cancer invasion zone, contradicting recent findings from organoid and xenograft animal models [5,18,19]. These results align with recent findings of neuronal transcriptomic signatures in GBM cells in this region [4,23,29], including NPC-like cell states [4].…”

Section: Discussioncontrasting

confidence: 68%

“…As hSyn and NeuN expression indicates neuronal lineage, hSyn1 + /NeuN + cells may represent neurons with an altered and aberrant electrophysiological phenotype due to GBM infiltration. The findings of hyperexcitability within the GBM-infiltrated region, may possibly be influenced by factors like paracrine glutamate secretion from GBM cells [34, 36], loss of GABAergic interneurons [37], glioma-induced neuronal synaptic remodeling using GPC3 as a driver [38], and alterations of potassium handling through the interaction between IGSF3 and Kir4.1 channels [18, 35]. Alternatively, hSyn1 + /NeuN + cells may represent an NPC-like cellular state of GBM, which is commonly known to be enriched at the leading tumor edge [4, 23].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, it is unclear if GBM cells at the tumor edge have excitable membranes potentially enabling active integration into the surrounding tumor network and adjacent brain tissue. Preliminary analyses based on animal models and GBM cell lines have indicated a non-excitable nature of GBM cells [5, 18, 19], akin to astrocytes [20]. Conversely, one study on acute human GBM-infiltrated brain slices reported action potentials (APs) in presumed tumor cells with abnormal bipolar and multipolar morphology expressing typical glial markers, such as glial fibrillary acidic protein (GFAP) [21].…”

Section: Mainmentioning

confidence: 99%

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Glioblastoma cells imitate neuronal excitability in humans

Tong,

Ozsvar,

Eschen

et al. 2024

Preprint

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SummaryGlioblastomas (GBM) are renowned for their pronounced intratumoral heterogeneity, characterized by a diverse array of plastic cell types, which poses a significant challenge to effective targeting and treatment [1]. Recent research has documented the presence of neuronal-progenitor-like transcriptomic cell states of GBM [2, 3], notably in the leading edge of the tumor, where synaptic input from adjacent neurons drives disease proliferation [4]. However, conflicting observations regarding GBM cell excitability, ranging from non-excitable [5] to neuron-like excitability [6], add complexity to our comprehension of the pathophysiological diversity of GBM cells. Here we established a novel experimental workflow enabling comprehensive and selective investigation of the electrophysiological characteristics of cancer cells and neurons within cancer-infiltrated organotypic tissue specimens from GBM patients, using viral genetic labelling to target cellular subtypes. We observed that GBM cells exhibit distinct electrophysiological features in humans, characterized by hyperexcitability and neuron-like action potential generation. Our research provides direct evidence of excitability and a comprehensive description of the electrophysiological characteristics of GBM cells in the cancer-infiltrated cortex of humans, contributing to a deeper understanding of the cellular biology of GBM. These insights have broader implications for understanding cell-cell interactions in malignant tumors and could inform targeted therapies across diverse cancer types, offering a new lens for tackling tumor heterogeneity.

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Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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Glioblastoma cells imitate neuronal excitability in humans

Tong,

Ozsvar,

Eschen

et al. 2024

Preprint

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“…These effects were accentuated when the cell was incubated with 60 mM [K + ] o . We next tested the effects of 0.2 mM Ba 2+ , a potent inward K + channel blocker (Madadi et al, 2021; Schram et al, 2003). Barium blocked both the inward and outward currents, but was much more potent at blocking the inward current (93% vs. 16%), indicating voltage‐dependent block.…”

Section: Resultsmentioning

confidence: 99%

Kir4.1 is specifically expressed and active in non‐myelinating Schwann cells

Procacci

Hastings

Aziz

et al. 2022

Glia

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Non-myelinating Schwann cells (NMSC) play important roles in peripheral nervous system formation and function. However, the molecular identity of these cells remains poorly defined. We provide evidence that Kir4.1, an inward-rectifying K+ channel encoded by the KCNJ10 gene, is specifically expressed and active in NMSC.Immunostaining revealed that Kir4.1 is present in terminal/perisynaptic SCs (TPSC), synaptic glia at neuromuscular junctions (NMJ), but not in myelinating SCs (MSC) of adult mice. To further examine the expression pattern of Kir4.1, we generated BAC transgenic Kir4.1-CreER T2 mice and crossed them to the tdTomato reporter line. Activation of CreER T2 with tamoxifen after the completion of myelination onset led to robust expression of tdTomato in NMSC, including Remak Schwann cells (RSC) along peripheral nerves and TPSC, but not in MSC. In contrast, activating CreER T2 before and during the onset of myelination led to tdTomato expression in NMSC and MSC.These observations suggest that immature SC express Kir4.1, and its expression is then downregulated selectively in myelin-forming SC. In support, we found that while activating CreER T2 induces tdTomato expression in immature SC, it fails to induce tdTomato in MSC associated with sensory axons in culture. NMSC derived from neonatal sciatic nerve were shown to express Kir4.1 and exhibit barium-sensitive inwardly rectifying macroscopic K + currents. Thus, this study identified Kir4.1 as a potential modulator of immature SC and NMSC function. Additionally, it established a novel transgenic mouse line to introduce or delete genes in NMSC.

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“…These occur secondary to greater extracellular glutamate accumulation, as will be discussed later in glutamate release, reuptake, and post-synaptic action (Kucheryavykh et al, 2007 ; Armbruster et al, 2021 ). Both downregulation and mislocalization of Kir4.1 has been demonstrated in patient-derived GBM samples and cell lines (Zurolo et al, 2012 ; Madadi et al, 2021 ). As well as significant electrophysiological changes including a depolarized astrocytic RMP and large outward K + currents (Olsen and Sontheimer, 2004 ).…”

Section: Factors Contributing To Tumor-driven Epileptogenesismentioning

confidence: 99%

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

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Correlation between Kir4.1 expression and barium-sensitive currents in rat and human glioma cell lines

Cited by 5 publications

References 27 publications

Glioblastoma cells imitate neuronal excitability in humans

Glioblastoma cells imitate neuronal excitability in humans

Kir4.1 is specifically expressed and active in non‐myelinating Schwann cells

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

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