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

Mark A. Prendergast, D. Trent Rogers, Patrick J. Mulholland, John M. Littleton, Lincoln H. Wilkins, Rachel L. Self, Avindra Nath

Research output: Contribution to journalArticle

Abstract

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 μM) 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 μM. Tat potently inhibited the potentiation of [3H]MK-801 binding produced by co-exposure of membranes to the NMDAr co-agonist spermidine (IC50=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 μM) and the NMDAr polyamine-site antagonist arcaine (10 μM). Exposure to the HIV-1 Tat deletion mutant (TatΔ31-61) 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.

Original languageEnglish (US)
Pages (from-to)300-307
Number of pages8
JournalBrain Research
Volume954
Issue number2
DOIs
StatePublished - Nov 8 2002

Fingerprint

Polyamines
N-Methyl-D-Aspartate Receptors
HIV-1
Transcription Factors
Dizocilpine Maleate
Spermidine
Hippocampal CA3 Region
tat Gene Products
Hippocampal CA1 Region
Aptitude
Dentate Gyrus
Brain
Cerebral Cortex
Cerebellum
Inhibitory Concentration 50
HIV Infections
Dementia
Hippocampus
HIV
Membranes

Keywords

  • Acquired immune deficiency syndrome
  • Dementia
  • Excitotoxicity
  • Polyamine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Prendergast, Mark A.; Rogers, D. Trent; Mulholland, Patrick J.; Littleton, John M.; Wilkins, Lincoln H.; Self, Rachel L.; Nath, Avindra.

In: Brain Research, Vol. 954, No. 2, 08.11.2002, p. 300-307.

Research output: Contribution to journalArticle

Prendergast, Mark A. ; Rogers, D. Trent ; Mulholland, Patrick J. ; Littleton, John M. ; Wilkins, Lincoln H. ; Self, Rachel L. ; Nath, Avindra. / 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. In: Brain Research. 2002 ; Vol. 954, No. 2. pp. 300-307.
@article{9cb18ae2ba4942868b661689aa4f48f5,
title = "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",
abstract = "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 μM) 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 μM. Tat potently inhibited the potentiation of [3H]MK-801 binding produced by co-exposure of membranes to the NMDAr co-agonist spermidine (IC50=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 μM) and the NMDAr polyamine-site antagonist arcaine (10 μM). Exposure to the HIV-1 Tat deletion mutant (TatΔ31-61) 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.",
keywords = "Acquired immune deficiency syndrome, Dementia, Excitotoxicity, Polyamine",
author = "Prendergast, {Mark A.} and Rogers, {D. Trent} and Mulholland, {Patrick J.} and Littleton, {John M.} and Wilkins, {Lincoln H.} and Self, {Rachel L.} and Avindra Nath",
year = "2002",
month = "11",
day = "8",
doi = "10.1016/S0006-8993(02)03360-7",
language = "English (US)",
volume = "954",
pages = "300--307",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - 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

AU - Prendergast, Mark A.

AU - Rogers, D. Trent

AU - Mulholland, Patrick J.

AU - Littleton, John M.

AU - Wilkins, Lincoln H.

AU - Self, Rachel L.

AU - Nath, Avindra

PY - 2002/11/8

Y1 - 2002/11/8

N2 - 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 μM) 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 μM. Tat potently inhibited the potentiation of [3H]MK-801 binding produced by co-exposure of membranes to the NMDAr co-agonist spermidine (IC50=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 μM) and the NMDAr polyamine-site antagonist arcaine (10 μM). Exposure to the HIV-1 Tat deletion mutant (TatΔ31-61) 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.

AB - 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 μM) 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 μM. Tat potently inhibited the potentiation of [3H]MK-801 binding produced by co-exposure of membranes to the NMDAr co-agonist spermidine (IC50=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 μM) and the NMDAr polyamine-site antagonist arcaine (10 μM). Exposure to the HIV-1 Tat deletion mutant (TatΔ31-61) 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.

KW - Acquired immune deficiency syndrome

KW - Dementia

KW - Excitotoxicity

KW - Polyamine

UR - http://www.scopus.com/inward/record.url?scp=0037044856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037044856&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(02)03360-7

DO - 10.1016/S0006-8993(02)03360-7

M3 - Article

VL - 954

SP - 300

EP - 307

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 2

ER -