Molecular interactions of the type 1 human immunodeficiency virus transregulatory protein Tat with N-methyl-d-aspartate receptor subunits

T Chandra, W Maier, H-G König, K Hirzel, D Kögel, T Schüler, A Chandra, I Demirhan, B Laube

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

We investigated the effect of type 1 human immunodeficiency virus (HIV-1) regulatory protein Tat on N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes by voltage-clamp recording and its role in NMDA-mediated neurotoxicity using cultured rat hippocampal neurons. Tat (0.01-1muM) potentiated NMDA-induced currents of recombinant NMDA receptors. However, in the presence of Zn(2+), the potentiating effect of Tat was much more pronounced, indicating an additional Zn(2+)-related effect on NMDA receptors. Consistently, Tat potentiated currents of the particularly Zn(2+)-sensitive NR1/NR2A NMDA receptor with a higher efficacy, whereas currents from a Zn(2+)-insensitive mutant were only marginally augmented. In addition, chemical-modified Tat, deficient for metal binding, did not reverse Zn(2+)-mediated inhibition of NMDA responses, demonstrating that Tat disinhibits NMDA receptors from Zn(2+)-mediated antagonism by complexing the cation. We therefore investigated the interplay of Tat and Zn(2+) in NMDA-mediated neurotoxicity using cultures of rat hippocampal neurons. Zn(2+) exhibited a prominent rescuing effect when added together with the excitotoxicant NMDA, which could be reverted by the Zn(2+)-chelator tricine. Similar to tricine, Tat enhanced NMDA-mediated neurotoxicity in the presence of neuroprotective Zn(2+) concentrations. Double-staining with antibodies against Tat and the NR1 subunit of the NMDA receptor revealed partial colocalization of the immunoreactivities in membrane patches of hippocampal neurons, supporting the idea of a direct interplay between Tat and glutamatergic transmission. We therefore propose that release of Zn(2+)-mediated inhibition of NMDA receptors by HIV-1 Tat contributes to the neurotoxic effect of glutamate and may participate in the pathogenesis of AIDS-associated dementia.

Original languageEnglish
Pages (from-to)145-53
Number of pages9
JournalNeuroscience
Volume134
Issue number1
DOIs
Publication statusPublished - 2005

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Animals, Newborn
  • Chromatin
  • Drug Interactions
  • Gene Products, tat
  • Glycine
  • Hippocampus
  • Humans
  • Immunohistochemistry
  • Membrane Potentials
  • Microinjections
  • Microscopy, Confocal
  • Mutagenesis
  • N-Methylaspartate
  • Neurons
  • Oocytes
  • Patch-Clamp Techniques
  • Protein Subunits
  • Rats
  • Receptors, N-Methyl-D-Aspartate
  • Toxoids
  • Xenopus
  • Zinc

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