Neurotoxic effects of the human immunodeficiency virus type-1 transcription factor Tat require function of a polyamine sensitive-site on the N-methyl-D-aspartate receptor.
Human immunodeficiency virus type-I (HIV-1) infection is often associated with neuronal loss in cortical and subcortical regions that may manifest as motor dysfunction and dementia. The function of the HIV-1 transcription protein Tat and subsequent activation of N-methyl-D-aspartate receptors (NMDAr) have been implicated in this form of neurodegeneration. However, it is unclear if Tat interacts directly with the NMDAr and the role of specific NMDAr subunit composition in mediating effects of Tat is also unclear. The present studies examined the ability of HIV-1 Tat1-72 protein (10 pM-1.0 microM) to displace [3H]MK-801 binding and to attenuate spermidine-induced potentiation of this binding in rat brain homogenate comprised of cerebellum, hippocampus, and cerebral cortex. The role of NMDAr polyamine-site function in the neurotoxic effects of Tat was determined using organotypic hippocampal slice cultures. Binding of [3H]MK-801 in adult rat brain homogenate was not reduced by Tat at concentrations below 1 microM. Tat potently inhibited the potentiation of [3H]MK-801 binding produced by co-exposure of membranes to the NMDAr co-agonist spermidine (IC(50)=3.74 nM). In hippocampal explants, Tat produced neurotoxicity in the CA3 and CA1 pyramidal cell layers, as well as in the dentate gyrus, that was significantly reduced by co-exposure to MK-801 (20 microM) and the NMDAr polyamine-site antagonist arcaine (10 microM). Exposure to the HIV-1 Tat deletion mutant (Tatdelta31-61) did not produce neurotoxicity in hippocampal explants. These data suggest that the neurotoxic effects of HIV-1 Tat are mediated, in part, by direct interactions with a polyamine-sensitive site on the NMDAr that positively modulates the function of this receptor.
Prendergast
Mark A
MA
Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, USA. prender@pop.uky.edu
Rogers
D Trent
DT
Mulholland
Patrick J
PJ
Littleton
John M
JM
Wilkins
Lincoln H
LH
Self
Rachel L
RL
Nath
Avindra
A
D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D002531:Cerebellum / Q000378:metabolism / Q000821:virology; D002540:Cerebral Cortex / Q000378:metabolism / Q000821:virology; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015497:HIV-1 / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000821:virology; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000821:virology; D009498:Neurotoxins / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013095:Spermidine / Q000494:pharmacology*
D001645:Biguanides; D004268:DNA-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; C006624:arcaine; D016291:Dizocilpine Maleate; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C064757:PSMC3 protein, human; D013095:Spermidine