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

Jianuo Liu, Peng Xu, Cory Collins, Han Liu, Jingdong Zhang, James P. Keblesh, Huangui Xiong

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv 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 Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K+ channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 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 Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.

Original languageEnglish (US)
Article numbere64904
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 30 2013

Fingerprint

Human Immunodeficiency Virus tat Gene Products
tat Gene Products
neuroglia
Microglia
Human immunodeficiency virus 1
HIV-1
potassium channels
proteins
Chemical activation
4-aminopyridine
psoralen
Voltage-Gated Potassium Channels
Ficusin
4-Aminopyridine
nervous system diseases
Mitogen-Activated Protein Kinase 1
interleukin-1
transfection
small interfering RNA
Nervous System Diseases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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.

In: PloS one, Vol. 8, No. 5, e64904, 30.05.2013.

Research output: Contribution to journalArticle

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. In: PloS one. 2013 ; Vol. 8, No. 5.
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