HIV-1 gp120 enhances outward potassium current via CXCR4 and cAMP-dependent protein kinase a signaling in cultured rat microglia

Changshui Xu, Jianuo Liu, Lina Chen, Shangdong Liang, Nobutaka Fujii, Hirokazu Tamamura, Huangui Xiong

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Microglia are critical cells in mediating the pathophysiology of neurodegenerative disorders such as HIV-associated neurocognitive disorders. We hypothesize that HIV-1 glycoprotein 120 (gp120) activates microglia by enhancing outward K + currents, resulting in microglia secretion of neurotoxins, consequent neuronal dysfunction, and death. To test this hypothesis, we studied the effects of gp120 on outward K + current in cultured rat microglia. Application of gp120 enhanced outward K + current in a dose-dependent manner, which was blocked by voltage-gated K + (K v) channel blockers. Western blot analysis revealed that gp120 produced an elevated expression of K v channel proteins. Examination of activation and inactivation of outward K + currents showed that gp120 shifted membrane potentials for activation and steady-state inactivation. The gp120-associated enhancement of outward K + current was blocked by either a CXCR4 receptor antagonist T140 or a specific protein kinase A (PKA) inhibitor H89, suggesting the involvement of chemokine receptor CXCR4 and PKA in gp120-mediated enhancement of outward K + current. Biological significance of gp120-induced enhancement of microglia outward K + current was demonstrated by experimental results showing the neurotoxic activity of gp120-stimulated microglia, evaluated by TUNEL staining and MTT assay, significantly attenuated by K v channel blockers. Taken together, these results suggest that gp120 induces microglia neurotoxic activity by enhancing microglia outward K + current and that microglia K v channels may function as a potential target for the development of therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)997-1007
Number of pages11
JournalGlia
Volume59
Issue number6
DOIs
StatePublished - Jun 1 2011

    Fingerprint

Keywords

  • Chemokine receptors
  • Neurodegeneration
  • Neuronal apoptosis
  • Voltage-gated K channels

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this