Voltage-dependent calcium channel signaling mediates GABAAreceptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii

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Abstract

The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection, γ–aminobutyric acid (GABA)/GABAAreceptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAAreceptors by GABA induces transient Ca2+entry in DCs. Murine bone marrow-derived DCs preferentially expressed the L-type voltage-dependent Ca2+channel (VDCC) subtype Cav1.3. Silencing of Cav1.3 by short hairpin RNA or selective pharmacological antagonism of VDCCs abolished the Toxoplasma-induced hypermigratory phenotype. In a mouse model of toxoplasmosis, VDCC inhibition of adoptively transferred Toxoplasma-infected DCs delayed the appearance of cell-associated parasites in the blood circulation and reduced parasite dissemination to target organs. The present data establish that T. gondii-induced hypermigration of DCs requires signaling via VDCCs and that Ca2+acts as a second messenger to GABAergic signaling via the VDCC Cav1.3. The findings define a novel motility-related signaling axis in DCs and unveil that interneurons and DCs share common GABAergic motogenic pathways. T. gondii employs GABAergic non-canonical pathways to induce host cell migration and facilitate dissemination.

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Kanatani, S., Fuks, J. M., Olafsson, E. B., Westermark, L., Chambers, B., Varas-Godoy, M., … Barragan, A. (2017). Voltage-dependent calcium channel signaling mediates GABAAreceptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii. PLoS Pathogens, 13(12). https://doi.org/10.1371/journal.ppat.1006739

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