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

• Published in: Neuroscience 2005, Vol.134 (1), p.145-153
• Main Authors: Chandra, T., Maier, W., König, H.-G., Hirzel, K., Kögel, D., Schüler, T., Chandra, A., Demirhan, I., Laube, B.
• Format: Article
• Language: English
• Subjects: AIDS; Animals; Animals, Newborn; Biological and medical sciences; Chromatin; dementia; Drug Interactions; Fundamental and applied biological sciences. Psychology; Gene Products, tat - metabolism; Gene Products, tat - pharmacology; glutamate; Glycine - analogs & derivatives; Glycine - pharmacology; hippocampus; Hippocampus - cytology; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunohistochemistry - methods; Infectious diseases; Medical sciences; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membrane Potentials - radiation effects; Microinjections - methods; Microscopy, Confocal - methods; Mutagenesis - physiology; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - radiation effects; neurotoxicity; Oocytes; Patch-Clamp Techniques - methods; Protein Subunits - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - biosynthesis; Receptors, N-Methyl-D-Aspartate - metabolism; Tat-toxoid; Toxoids - pharmacology; Vertebrates: nervous system and sense organs; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Xenopus; Zinc - metabolism; Zinc - pharmacology
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2005.02.049

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 (0.01–1μM) 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.