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Regulation of neuronal proapoptotic potassium currents by the hepatitis C virus nonstructural protein 5A

Callie A Norris1, Kai He, Mitchell G Springer

  • 1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|June 30, 2012
PubMed

Insights

Hepatitis C virus protein NS5A1b protects neurons by reducing potassium (K+) currents, specifically inhibiting Kv2.1 phosphorylation at Y124. This mechanism enhances neuronal survival after injury.

Area of Science:

  • Neuroscience
  • Virology
  • Molecular Biology

Background:

  • Apoptosis involves potassium (K+) efflux mediated by enhanced K+ currents, particularly in neurons via Kv2.1 phosphorylation.
  • Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) can inhibit Kv2.1 currents and block cell death in hepatocytes.

Purpose of the Study:

  • To investigate the neuroprotective effects of HCV NS5A1b in rat neurons.
  • To determine the mechanism by which NS5A1b modulates Kv2.1 currents and neuronal survival.

Main Methods:

  • Expression of NS5A1b in rat neurons to assess its effect on delayed rectifier potassium currents.
  • Utilized a recombinant expression system with wild-type and mutated Kv2.1 channels (Y124F, S800F) to study NS5A1b interaction.
  • Investigated the impact of NS5A1b on Src and p38 phosphorylation of Kv2.1.

Main Results:

  • NS5A1b expression in neurons reduced delayed rectifier potassium currents and the K+ current surge post-microglial activation, conferring neuroprotection.
  • Mutations at Kv2.1 residue Y124, but not S800, rendered channels insensitive to NS5A1b-mediated current inhibition.
  • NS5A1b inhibited Src phosphorylation of Kv2.1 at Y124 but not p38 phosphorylation at S800; NS5A1a lacked these effects, showing genotype selectivity.

Conclusions:

  • HCV NS5A1b limits K+ currents following neuronal injury, thereby increasing neuronal viability.
  • NS5A1b's genotype-specific inhibition of Kv2.1 phosphorylation at Y124 offers a potential therapeutic strategy for neuroprotection.

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