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


Chandra T., Maier W., Konig H., Hirzel K., Kogel D., Schuler T., ...More

NEUROSCIENCE, vol.134, no.1, pp.145-153, 2005 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 134 Issue: 1
  • Publication Date: 2005
  • Doi Number: 10.1016/j.neuroscience.2005.02.049
  • Title of Journal : NEUROSCIENCE
  • Page Numbers: pp.145-153

Abstract

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-mecliated neurotoxicity using cultured rat hippocampal neurons. Tat (0.01-1 mu M) potentiated NMDA-induced currents of recombinant NMDA receptors. However, in the presence of Zn2+, the potentiating effect of Tat was much more pronounced, indicating an additional Zn2+-related effect on NMDA receptors. Consistently, Tat potentiated currents of the particularly Zn2+-sensitive NR1/NR2A NMDA receptor with a higher efficacy, whereas currents from a Zn2+-insensitive mutant were only marginally augmented. In addition, chemical-modified Tat, deficient for metal binding, did not reverse Zn2+-mediated inhibition of NMDA responses, demonstrating that Tat disinhibits NMDA receptors from Zn2+-mediated antagonism by complexing the cation. We therefore investigated the interplay of Tat and Zn2+ in NMDA-mediated neurotoxicity using cultures of rat hippocampal neurons. Zn2+ exhibited a prominent rescuing effect when added together with the excitotoxicant NMDA, which could be reverted by the Zn2+ chelator tricine. Similar to tricine, Tat enhanced NMDA-mediated neurotoxicity in the presence of neuroprotective Zn2+ 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 Zn2+-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. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.