Ion Channels in Glioma Malignancy

Catacuzzeno, Luigi; Sforna, Luigi; Esposito, Vincenzo; Limatola, Cristina; Franciolini, Fabio

doi:10.1007/112_2020_44

Cited by 27 publications

(24 citation statements)

References 240 publications

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“…It was reported that calcium ions play a primordial role in glioblastoma cell motility [ 38 , 39 ]. It has been demonstrated that the expression of modulators of calcium flux on glioblastoma cells, such as FPRL-1 (formyl peptide receptor-like 1), GluRs (Glutamyl-tRNA synthetase) and P2 × 7R (an ATP-gated nonselective cation channel) along with voltage-gated calcium channel, activate the signaling pathways of MAP Kinases, as well as AKT and PI3K, hence triggering survival, growth and mobility of GMB cells [ 4 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

et al. 2022

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Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC50 value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.

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Section: Discussionmentioning

confidence: 99%

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

et al. 2022

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“…In a similar manner, targeting KCa3.1 channels has been proposed as a strategy for pharmacological intervention in glioblastoma [90], in that the channel is also highly expressed and of likely importance in that tumor [91]. From a practical point of view, as highlighted by Brown et al [90], senicapoc has already been tested in Phase III clinical trials, and would therefore be available for repurposing.…”

Section: Discussionmentioning

confidence: 99%

TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

Ferrera

Barbieri

Picco

et al. 2021

IJMS

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Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline—a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc—a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole—two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.

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“…Our laboratory has also developed a model of voltage gating, based on both the Poisson-Nernst-Planck formalism for the description of ion electrodiffusion and the assessment of the electrostatic potential, and the Brownian dynamics for the description of the voltage sensor movements (Catacuzzeno & Franciolini, 2019;Catacuzzeno et al, 2020). The geometry and charge distribution of the model were derived from a Shaker atomic structure obtained by homology modelling from the crystallographic structure of the Kv1.2/2.1 chimera (Long et al, 2007).…”

Section: Other Approaches To Modelling Channel Gatingmentioning

confidence: 99%

The 70‐year search for the voltage‐sensing mechanism of ion channels

Catacuzzeno

Franciolini

2022

The Journal of Physiology

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This retrospective on the voltage‐sensing mechanisms and gating models of ion channels begins in 1952 with the charged gating particles postulated by Hodgkin and Huxley, viewed as charges moving across the membrane and controlling its permeability to Na+ and K+ ions. Hodgkin and Huxley postulated that their movement should generate small and fast capacitive currents, which were recorded 20 years later as gating currents. In the early 1980s, several voltage‐dependent channels were cloned and found to share a common architecture: four homologous domains or subunits, each displaying six transmembrane α‐helical segments, with the fourth segment (S4) displaying four to seven positive charges invariably separated by two non‐charged residues. This immediately suggested that this segment was serving as the voltage sensor of the channel (the molecular counterpart of the charged gating particle postulated by Hodgkin and Huxley) and led to the development of the sliding helix model. Twenty years later, the X‐ray crystallographic structures of many voltage‐dependent channels allowed investigation of their gating by molecular dynamics. Further understanding of how channels gate will benefit greatly from the acquisition of high‐resolution structures of each of their relevant functional or structural states. This will allow the application of molecular dynamics and other approaches. It will also be key to investigate the energetics of channel gating, permitting an understanding of the physical and molecular determinants of gating. The use of multiscale hierarchical approaches might finally prove to be a rewarding strategy to overcome the limits of the various single approaches to the study of channel gating.

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Ion Channels in Glioma Malignancy

Cited by 27 publications

References 240 publications

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

The 70‐year search for the voltage‐sensing mechanism of ion channels

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