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

Chandra, Tamir; Maier, Wolfgang; König, H-G; Hirzel, Klaus; Kögel, Donat; Schüler, Thomas; Chandra, Angelika; Demirhan, Ilhan; Laube, Bodo

doi:10.1016/j.neuroscience.2005.02.049

Cited by 35 publications

(39 citation statements)

References 42 publications

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“…But instead Tat-induced toxicity could be blocked by pharmacological blockers of NMDA receptor, which also suggests that the interactions of Tat with NMDA receptor are specific. These findings are consistent with studies showing that Tat can be colocalized to the NMDA receptor by immunostaining on the cell surface of neurons (Chandra et al, 2005) and suggest that the binding properties of Tat are specific for the NMDA receptor.…”

Section: Discussionsupporting

confidence: 91%

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NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Li¹,

et al. 2008

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Section: Discussionsupporting

confidence: 91%

“…suggests that Tat may act at another site on the NMDA receptor (Chandra et al, 2005). In modeling the interactions of Tat with the NMDA receptor we considered the possibility that a large ligand such as Tat protein might anchor itself to the cell membrane and then Cys31 might interact with the receptor to activate it.…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Li¹,

et al. 2008

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“…Interactions of Tat with neuronal membrane-bound receptors play an essential role in the mechanism of Tat neurotoxicity (Strijbos et al, 1995;Wallace et al, 2006(a,b); Chandra et al, 2005). Previous studies in different cell culture models have focused on the role of NMDA receptor-controlled pathways in the mechanism of Tat neurotoxicity (King et al, 2006;Perez et al, 2001;Wang et al, 1999;Magnuson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity of HIV-1 Tat protein: Involvement of D1 dopamine receptor☆

Silvers¹,

Aksenova²,

Aksenov³

et al. 2007

NeuroToxicology

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Neurotoxic viral proteins released from HIV-infected cells are believed to play a major role in the pathogenesis of the dementia displayed in a significant number of AIDS patients. HIV-1 associated neuropathology severely affects dopaminergic regions of the brain. Growing evidence indicates that HIV-1 neurotoxic proteins, such as Tat may affect the function of the dopamine transmission system. In turn, molecular components of dopamine neurotransmission may participate in a complex network of Tat-induced cell responses which result in neurodegeneration. In this study we investigated whether D1 dopamine receptors are involved in the mechanism of Tat neurotoxicity in primary rat neuronal cell cultures. We found that in rat midbrain cell cultures, which express significant levels of D1 dopamine receptors, the specific D1 antagonist SCH 23390 attenuates the cell death caused by HIV-1 Tat. In rat hippocampal cell cultures, where the expression of D1 receptors is low, SCH 23390 did not change the toxicity of Tat. Thus, the protective effect of SCH 23390 in rat primary neuronal cell cultures correlates with the level of D1 receptor protein expression. Our results provide further evidence for the involvement of the dopaminergic transmission system in the mechanism of HIV-1 Tat neurotoxicity.

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“…One study showed that clade B Tat exerts a neurotoxic effect on rat hippocampal neurons by binding zinc and thus reversing zinc antagonism of NMDAR, thereby potentiating NMDA-mediated excitotoxic cell death. 23 In another study, both clade B and clade C Tat were shown to be similarly secreted from infected cells and that both clades of Tat bind NMDAR with the same efficiency, but induce different levels of excitotoxicity. 28 Interestingly, the intact C30C31 motif found in clade B Tat was shown to be critical for exciting the NMDAR, whereas the C31S mutation, found in over 90% of clade C Tat proteins, significantly attenuated this neurotoxic response.…”

Section: Introductionmentioning

confidence: 97%

“…14,15 In studies of clade B Tat, it is unknown whether it is released by infected cells in situ or is transported across the blood-brain barrier, 16 but it is detectable within the brains of infected individuals [17][18][19][20] where it has neurotoxic consequences. 13,[21][22][23][24][25][26] Indeed, a single intraventricular injection of clade B Tat leads to pathologies observed in HAD, namely, macrophage infiltration, progressive glial activation, and neuronal cell death. 27 The effect of clade B Tat on neuronal apoptosis is thought to be dependent on Tat binding the lipoprotein-related protein receptor and activating the Ca 2þ -permeable N-methyl-daspartate (NMDA) receptors (NMDAR).…”

Section: Introductionmentioning

confidence: 99%

Differential Induction of Rat Neuronal Excitotoxic Cell Death by Human Immunodeficiency Virus Type 1 Clade B and C Tat Proteins

Campbell

Watkins

Loret

et al. 2011

AIDS Research and Human Retroviruses

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In the absence of effective antiretroviral therapy, infection with clade B human immunodeficiency virus (HIV-1) infection commonly progresses to AIDS dementia. However, in India, where clade C infection is most prevalent, severe cognitive impairment due to HIV-1 is reported to be less prevalent. The Tat protein of HIV-1, which is released from HIV-1-infected macrophages, is thought to play a major role in the disruption of neuronal function as well as in the infiltration of macrophages associated with advanced neuropathogenesis. Clade B Tat is excitotoxic to hippocampal neurons by potentiating N-methyl-d-aspartate-induced currents of the zinc-sensitive NR1/NR2A N-methyl-d-aspartate receptor in a zinc-binding-dependent mechanism. This study characterizes the zinc-binding properties of clade C Tat protein. Using ultraviolet spectroscopy and the Ellman reaction, we show that clade C Tat protein binds just one zinc ion per monomer. We then investigated the ability of clade C Tat to block the inhibition of N-methyl-d-aspartate receptors from zinc antagonism through ion chelation. Although clade C Tat enhanced N-methyl-d-aspartate-mediated rat hippocampus neuronal toxicity in the presence of zinc, the increase was significantly less than that observed with clade B Tat. These findings suggest that the observed differences in neuropathogenesis found with HIV-1 clade C infection compared to clade B may, in part, be due to a decrease in Tat-mediated neurotoxicity.

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

Cited by 35 publications

References 42 publications

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Neurotoxicity of HIV-1 Tat protein: Involvement of D1 dopamine receptor☆

Differential Induction of Rat Neuronal Excitotoxic Cell Death by Human Immunodeficiency Virus Type 1 Clade B and C Tat Proteins

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