Squaring the Circle: A New Study of Inward and Outward-Rectifying Potassium Currents in U251 GBM Cells

Ratto, Daniela; Ferrari, Béatrice; Roda, Elisa; Brandalise, Federico; Siciliani, Stella; Luca, Fabrizio De; Priori, Erica Cecilia; Iorio, Carmine Di; Cobelli, Filippo; Veneroni, Paola; Bottone, Maria Grazia; Rossi, Paola

doi:10.1007/s10571-019-00776-3

Cited by 10 publications

(22 citation statements)

References 41 publications

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“…Indeed, despite the fact that the mechanism is not yet understood, in Ratto et al, 2019, a calcium-dependent upregulation of Kir4.1mediated current has been described within 9 min of menthol bath-application. • The simultaneous block of Kir4.1 along with the BK channel seems to be an effective strategy for blocking GBM cell invasiveness in two-dimensional migration assays without additional perturbation (raising) of the cytosolic calcium concentration (Ratto et al, 2019). This suggests that the two classes of potassium channels are mutually involved in the shrinkage of the cell via regulation of the K + gradient.…”

Section: Kir41 In Globlastoma: Primum Movens Of Rmp Depolarization Imentioning

confidence: 99%

“…Blockade of BK channels with iberiotoxin (IbTx) or tetraethylammonium (TEA) in two-dimensional migration assays inhibits GBM cell motility (Soroceanu et al, 1999;Basrai et al, 2002;Weaver et al, 2006). Furthermore, the increase of intracellular calcium induced by extracellular menthol application significantly increases BK current and the migration of GBM cells and this effect was reversed by BK channel blockers (Wondergem and Bartley, 2009;Ratto et al, 2019).…”

Section: Trying To Explain the Bk Role At The Gbm Rmpmentioning

confidence: 99%

“…In GBM, a downregulation of Kir4.1 during the early stage of the tumor progression has been reported (Olsen and Sontheimer, 2004;Ratto et al, 2019), which is correlated to the dramatic shift in RMP of GBM cells to more depolarized values around −40/−30 mV (Olsen and Sontheimer, 2004). Due to their internalization during GBM progression, very little attention has been paid to the residual activity of the Kir4.1 channels at RMP.…”

Section: Kir41 In Globlastoma: Primum Movens Of Rmp Depolarization Imentioning

confidence: 99%

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Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

et al. 2020

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In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.

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Section: Kir41 In Globlastoma: Primum Movens Of Rmp Depolarization Imentioning

confidence: 99%

Section: Trying To Explain the Bk Role At The Gbm Rmpmentioning

confidence: 99%

Section: Kir41 In Globlastoma: Primum Movens Of Rmp Depolarization Imentioning

confidence: 99%

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Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

et al. 2020

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“…Finally, TRPM8 channel might also modulate proliferation by dynamically control glioma resting potentials levels, which are key regulator of cell cycle. TRPM8 agonists have been shown to increase the Kir4.1 mediated membrane conductances of glioma cells (Ratto et al, 2020). Kir4.1 is an inward rectifier K + channel, with an altered pattern of expression in glioma.…”

Section: Melastatin Trpsmentioning

confidence: 99%

TRP Channels in Brain Tumors

Chinigò

Castel

Chever

et al. 2021

Front. Cell Dev. Biol.

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Malignant glioma including glioblastoma (GBM) is the most common group of primary brain tumors. Despite standard optimized treatment consisting of extensive resection followed by radiotherapy/concomitant and adjuvant therapy, GBM remains one of the most aggressive human cancers. GBM is a typical example of intra-heterogeneity modeled by different micro-environmental situations, one of the main causes of resistance to conventional treatments. The resistance to treatment is associated with angiogenesis, hypoxic and necrotic tumor areas while heterogeneity would accumulate during glioma cell invasion, supporting recurrence. These complex mechanisms require a focus on potential new molecular actors to consider new treatment options for gliomas. Among emerging and underexplored targets, transient receptor potential (TRP) channels belonging to a superfamily of non-selective cation channels which play critical roles in the responses to a number of external stimuli from the external environment were found to be related to cancer development, including glioma. Here, we discuss the potential as biological markers of diagnosis and prognosis of TRPC6, TRPM8, TRPV4, or TRPV1/V2 being associated with glioma patient overall survival. TRPs-inducing common or distinct mechanisms associated with their Ca2+-channel permeability and/or kinase function were detailed as involving miRNA or secondary effector signaling cascades in turn controlling proliferation, cell cycle, apoptotic pathways, DNA repair, resistance to treatment as well as migration/invasion. These recent observations of the key role played by TRPs such as TRPC6 in GBM growth and invasiveness, TRPV2 in proliferation and glioma-stem cell differentiation and TRPM2 as channel carriers of cytotoxic chemotherapy within glioma cells, should offer new directions for innovation in treatment strategies of high-grade glioma as GBM to overcome high resistance and recurrence.

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“…signalling in astrocytes is linked to an increase of K + uptake in hippocampus (Wang et al, 2012a) and cerebellum (Wang et al, 2012b). This astrocytic Ca Kir4.1 current from a U251 cell line (Ratto et al, 2020). Because (i) the locomotor-like activity is associated with [K + ] e homeostasis (Brocard et al, 2013), and (ii) the astrocytic K + uptake is activated by intracellular Ca 2+ transients (Wang et al, 2012a), we assume that the Ca 2+ dependent astrocytic K + homeostasis plays a key role in the spinal rhythmicity.…”

Section: +mentioning

confidence: 98%

Astrocytes regulate locomotion by orchestrating neuronal rhythmicity in the spinal network via potassium clearance

Barbay

Pecchi

Ducrocq

et al. 2022

Preprint

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Neuronal rhythmogenesis in the spinal cord is correlated with variations in extracellular K+ levels ([K+]e). Astrocytes play important role in[K+]e homeostasis and compute neuronal information. Yet it is unclear how neuronal oscillations are regulated by astrocytic K+ homeostasis. Here we identify the astrocytic inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) as a key molecular player for neuronal rhythmicity in the spinal central pattern generator (CPG). By combining two-photon calcium imaging with electrophysiology, immunohistochemistry and genetic tools, we report that astrocytes display Ca2+ transients before and during oscillations of neighbouring neurons. Inhibition of astrocytic Ca2+ transients with BAPTA decreases the barium-sensitive Kir4.1 current responsible of K+ clearance. Finally, we show in mice that Kir4.1 knockdown in astrocytes progressively prevents neuronal oscillations and alters the locomotor pattern resulting in lower motor performances in challenging tasks. These data identify astroglial Kir4.1 channels as key regulators of neuronal rhythmogenesis in the CPG driving locomotion.

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Squaring the Circle: A New Study of Inward and Outward-Rectifying Potassium Currents in U251 GBM Cells

Cited by 10 publications

References 41 publications

Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

TRP Channels in Brain Tumors

Astrocytes regulate locomotion by orchestrating neuronal rhythmicity in the spinal network via potassium clearance

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