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

Autor: Jingdong Zhang, Han Liu, James Keblesh, Jianuo Liu, Peng Xu, Huangui Xiong, Cory Collins
Rok vydání: 2013
Předmět:
Small interfering RNA
Anatomy and Physiology
Neuroimmunology
lcsh:Medicine
Toxicology
Ion Channels
Rats
Sprague-Dawley
chemistry.chemical_compound
0302 clinical medicine
Immunodeficiency Viruses
Immune Physiology
Molecular Cell Biology
Neurobiology of Disease and Regeneration
lcsh:Science
Mitogen-Activated Protein Kinase 1
Neurons
0303 health sciences
Kv1.3 Potassium Channel
Mitogen-Activated Protein Kinase 3
Multidisciplinary
Microglia
Up-Regulation
3. Good health
Cell biology
medicine.anatomical_structure
Biochemistry
Gene Knockdown Techniques
Medicine
Infectious diseases
tat Gene Products
Human Immunodeficiency Virus
HIV clinical manifestations
Cellular Types
Research Article
medicine.drug
Neurotoxicology
MAP Kinase Signaling System
Immune Cells
Neurotoxins
Immunology
Viral diseases
Biology
Microbiology
Nitric oxide
03 medical and health sciences
Downregulation and upregulation
Virology
Potassium Channel Blockers
medicine
Animals
Channel blocker
030304 developmental biology
lcsh:R
Margatoxin
HIV
Potassium channel blocker
Immunologic Subspecialties
Electrophysiological Phenomena
Rats
nervous system
chemistry
Apoptosis
Cellular Neuroscience
HIV-1
Potassium
Clinical Immunology
lcsh:Q
030217 neurology & neurosurgery
Neuroscience
Zdroj: PLoS ONE, Vol 8, Iss 5, p e64904 (2013)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0064904
Popis: 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.
Databáze: OpenAIRE
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