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

Scientific Reports
Alfonso GrimaldiM Catalano

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 Kv...Continue Reading

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Citations

Apr 28, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Xuejiao DongWanli Liu
Dec 14, 2018·Frontiers in Cellular Neuroscience·Starlee LivelyLyanne C Schlichter
Nov 26, 2020·Trends in Neurosciences·Lisa NielandErik R Abels
Apr 22, 2021·Cardiovascular Research·Roland ImmlerMarkus Sperandio

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Methods Mentioned

BETA
immunoprecipitation
GAM
PCR
Reverse

Software Mentioned

Metafluor
Quantity One
Patch Master
Clampex
Microcal Origin
Clampfit
SigmaPlot
MetaMorph
pCLAMP

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