Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity

Cell Death Dis. 2012 Jan 19;3(1):e254. doi: 10.1038/cddis.2011.140.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis* / drug effects
  • Cells, Cultured
  • Gene Expression Regulation
  • Gene Silencing
  • HIV Envelope Protein gp120 / pharmacology
  • HIV Envelope Protein gp120 / physiology*
  • Humans
  • Kv1.3 Potassium Channel / antagonists & inhibitors
  • Kv1.3 Potassium Channel / genetics
  • Kv1.3 Potassium Channel / metabolism*
  • Microglia / cytology
  • Microglia / drug effects*
  • Microglia / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurotoxins / pharmacology
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Scorpion Venoms / pharmacology
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • HIV Envelope Protein gp120
  • Kv1.3 Potassium Channel
  • Neurotoxins
  • Potassium Channel Blockers
  • RNA, Messenger
  • RNA, Small Interfering
  • Scorpion Venoms
  • margatoxin
  • p38 Mitogen-Activated Protein Kinases