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Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity
1Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Abstract:
Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K(+) (K(v)) channels are involved in the regulation of microglia functionality. In this study, we investigated K(v)1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of K(v)1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia K(v)1.3 current, which was blocked by margatoxin, a K(v)1.3 blocker. The association of gp120 enhancement of K(v)1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia K(v)1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of K(v)1.3 gene by transfection of microglia with K(v)1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia K(v)1.3 expression and resultant neurotoxic activity. These results suggest not only a role K(v)1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies.
Insights
Voltage-gated K(+) 1.3 (K(v)1.3) channels regulate neurotoxic activity in microglia stimulated by HIV-1 gp120. Blocking these channels reduces neurotoxin production, suggesting K(v)1.3 as a therapeutic target for HIV-1-associated neurocognitive disorders.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia activation is central to HIV-1-associated neurocognitive disorders.
- Voltage-gated K(+) (K(v)) channels influence microglia function.
- HIV-1 glycoprotein 120 (gp120) is implicated in neuroinflammation.
Purpose of the Study:
- To investigate the role of K(v)1.3 channels in gp120-stimulated microglia neurotoxicity.
- To identify K(v)1.3 as a potential therapeutic target for HIV-1 neurological complications.
Main Methods:
- Primary rat microglia cultures were treated with gp120.
- K(v)1.3 expression and current were measured using RT-qPCR, Western blot, and patch-clamp electrophysiology.
- Neurotoxicity was assessed by measuring neurotoxin production.
- K(v)1.3 was blocked using margatoxin or gene knockdown with siRNA.
- p38 MAPK involvement was investigated.
Main Results:
- gp120 increased K(v)1.3 mRNA and protein expression in microglia.
- gp120 enhanced K(v)1.3 channel currents, which were blocked by margatoxin.
- Blocking K(v)1.3 attenuated gp120-induced neurotoxin production and neurotoxicity.
- K(v)1.3 gene knockdown abrogated gp120-associated microglia neurotoxicity.
- p38 MAPK signaling pathway was involved in gp120-mediated K(v)1.3 upregulation.
Conclusions:
- K(v)1.3 channels play a critical role in mediating neurotoxic activity of microglia stimulated by HIV-1 gp120.
- K(v)1.3 channels represent a potential therapeutic target for mitigating neuroinflammation and neurotoxicity in HIV-1-associated neurocognitive disorders.
- p38 MAPK signaling is a key pathway regulating K(v)1.3 expression and function in this context.
