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HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (K(v)) channels are involved in the regulation of microglia function, prompting us to hypothesize K(v) channels may also be involved in microglia...

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Autores principales: Liu, Jianuo, Xu, Peng, Collins, Cory, Liu, Han, Zhang, Jingdong, Keblesh, James P., Xiong, Huangui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667810/
https://www.ncbi.nlm.nih.gov/pubmed/23738010
http://dx.doi.org/10.1371/journal.pone.0064904
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author Liu, Jianuo
Xu, Peng
Collins, Cory
Liu, Han
Zhang, Jingdong
Keblesh, James P.
Xiong, Huangui
author_facet Liu, Jianuo
Xu, Peng
Collins, Cory
Liu, Han
Zhang, Jingdong
Keblesh, James P.
Xiong, Huangui
author_sort Liu, Jianuo
collection PubMed
description Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (K(v)) channels are involved in the regulation of microglia function, prompting us to hypothesize K(v) channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of K(v) channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K(+) current and K(v)1.3 channel expression. Suppression of microglial K(v)1.3 channel activity, either with K(v)1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K(+) channel blocker 4-Aminopyridine, or by knockdown of K(v)1.3 expression via transfection of microglia with K(v)1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K(+) channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with K(v)1.3 were investigated and enhancement of microglial K(v)1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial K(v)1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.
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spelling pubmed-36678102013-06-04 HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity Liu, Jianuo Xu, Peng Collins, Cory Liu, Han Zhang, Jingdong Keblesh, James P. Xiong, Huangui PLoS One Research Article Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (K(v)) channels are involved in the regulation of microglia function, prompting us to hypothesize K(v) channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of K(v) channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K(+) current and K(v)1.3 channel expression. Suppression of microglial K(v)1.3 channel activity, either with K(v)1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K(+) channel blocker 4-Aminopyridine, or by knockdown of K(v)1.3 expression via transfection of microglia with K(v)1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K(+) channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with K(v)1.3 were investigated and enhancement of microglial K(v)1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial K(v)1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders. Public Library of Science 2013-05-30 /pmc/articles/PMC3667810/ /pubmed/23738010 http://dx.doi.org/10.1371/journal.pone.0064904 Text en © 2013 Liu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Liu, Jianuo
Xu, Peng
Collins, Cory
Liu, Han
Zhang, Jingdong
Keblesh, James P.
Xiong, Huangui
HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title_full HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title_fullStr HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title_full_unstemmed HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title_short HIV-1 Tat Protein Increases Microglial Outward K(+) Current and Resultant Neurotoxic Activity
title_sort hiv-1 tat protein increases microglial outward k(+) current and resultant neurotoxic activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667810/
https://www.ncbi.nlm.nih.gov/pubmed/23738010
http://dx.doi.org/10.1371/journal.pone.0064904
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