HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity

N. J. Haughey, A. Nath, M. P. Mattson, J. T. Slevin, J. D. Geiger

Research output: Contribution to journalArticle

214 Scopus citations

Abstract

Toxic effects of HIV-1 proteins contribute to altered function and decreased survival of select populations of neurons in HIV-1-infected brain. One such HIV-1 protein, Tat, can activate calcium release from IP3-sensitive intracellular pools, induce calcium influx in neural cells, and, as a result, can increase neuronal cell death. Here, we provide evidence that Tat potentiates excitatory amino acid (glutamate and NMDA) triggered calcium flux, as well as glutamate- and staurosporine-mediated neurotoxicity. Calcium flux in cultured rat hippocampal neurons triggered by the transient application of glutamate or NMDA was facilitated by pre-exposure to Tat. Facilitation of glutamate-triggered calcium flux by Tat was prevented by inhibitors of ADP-ribosylation of Gi/Go proteins (pertussis toxin), protein kinase C (H7 and bisindolymide), and IP3-mediated calcium release (xestospongin C), but was not prevented by an activator of Gs (cholera toxin) or an inhibitor of protein kinase A (H89). Facilitation of NMDAtriggered calcium flux by Tat was reversed by inhibitors of tyrosine kinase (genestein and herbimycin A) and by an inhibitor of NMDA receptor function (zinc). Tat increased 32P incorporation into NMDA receptor subunits NR2A and NR2B and this effect was blocked by genestein. Subtoxic concentrations of Tat combined with subtoxic concentrations of glutamate or staurosporine increased neuronal cell death significantly. Together, these findings suggest that NMDA receptors play an important role in Tat neurotoxicity and the mechanisms identified may provide additional therapeutic targets for the treatment of HIV-1 associated dementia.

Original languageEnglish (US)
Pages (from-to)457-467
Number of pages11
JournalJournal of Neurochemistry
Volume78
Issue number3
DOIs
StatePublished - 2001

Keywords

  • AIDS dementia
  • Glutamate
  • HIV-1
  • NMDA
  • Phosphorylation
  • Tat

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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