Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma

Alfonso Grimaldi, Giuseppina D'Alessandro, Maria Amalia Di Castro, Clotilde Lauro, Vikrant Singh, Francesca Pagani, Luigi Sforna, Francesca Grassi, Silvia Di Angelantonio, Luigi Catacuzzeno, Heike Wulff, Cristina Limatola, Myriam Catalano

Research output: Contribution to journalArticle

Abstract

Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. Under pathological conditions, some functions of glial cells could be compromised, exacerbating the neurotoxic processes. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K+ channel Kv1.3. To this end we used in vitro and in vivo systems to model cell-to-cell interactions in tumoral conditions, using a specific inhibitor of Kv1.3 channels, 5-(4-phenoxybutoxy) psoralen (PAP-1). We demonstrated that PAP-1 increases astrocytic glutamate uptake, reduces glioma-induced neurotoxicity, and decreases microglial migration and phagocytosis. We also found in a tumor blood brain barrier model that Kv1.3 activity is required for its integrity. The crucial role of Kv1.3 channels as modulators of glial cell activity was confirmed in a mouse model of glioma, where PAP-1 treatment reduces tumor volume only in the presence of active glutamate transporters GLT-1. In the same mouse model, PAP-1 reduces astrogliosis and microglial infiltration. PAP-1 also reduces tumor cell invasion. All these findings point to Kv1.3 channels as potential targets to re-instruct glial cells toward their homeostatic functions, in the context of brain tumors.

Original languageEnglish
Article number7654
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Glioma
Neuroglia
Astrocytes
Amino Acid Transport System X-AG
Voltage-Gated Potassium Channels
Ficusin
Microglia
Tumor Burden
Blood-Brain Barrier
Phagocytosis
Brain Neoplasms
Cell Communication
Glutamic Acid
Neoplasms
Homeostasis
Brain

ASJC Scopus subject areas

  • General

Cite this

Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma. / Grimaldi, Alfonso; D'Alessandro, Giuseppina; Di Castro, Maria Amalia; Lauro, Clotilde; Singh, Vikrant; Pagani, Francesca; Sforna, Luigi; Grassi, Francesca; Di Angelantonio, Silvia; Catacuzzeno, Luigi; Wulff, Heike; Limatola, Cristina; Catalano, Myriam.

In: Scientific Reports, Vol. 8, No. 1, 7654, 01.12.2018.

Research output: Contribution to journalArticle

Grimaldi, A, D'Alessandro, G, Di Castro, MA, Lauro, C, Singh, V, Pagani, F, Sforna, L, Grassi, F, Di Angelantonio, S, Catacuzzeno, L, Wulff, H, Limatola, C & Catalano, M 2018, 'Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma', Scientific Reports, vol. 8, no. 1, 7654. https://doi.org/10.1038/s41598-018-25940-5
Grimaldi, Alfonso ; D'Alessandro, Giuseppina ; Di Castro, Maria Amalia ; Lauro, Clotilde ; Singh, Vikrant ; Pagani, Francesca ; Sforna, Luigi ; Grassi, Francesca ; Di Angelantonio, Silvia ; Catacuzzeno, Luigi ; Wulff, Heike ; Limatola, Cristina ; Catalano, Myriam. / Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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