HIV‐1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity

Haughey, Norman J.; Nath, Avindra; Mattson, Mark P.; Slevin, John T.; Geiger, Jonathan D.

doi:10.1046/j.1471-4159.2001.00396.x

Cited by 242 publications

(263 citation statements)

References 63 publications

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“…Our data together with the observation that tyrosine phosphorylation of the NMDA receptor have been also implicated in exacerbation of neuronal cell loss induced by the pathogenic HIV-1 protein TAT (67), suggest a possible involvement of this pathway in HAD as well. Accordingly, we show that Ca-pYEEIE prevents neuronal death.…”

Section: Discussionsupporting

confidence: 58%

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Viviani¹,

Gardoni²,

Bartesaghi

et al. 2006

Journal of Biological Chemistry

108

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Interleukin-1␤ is a proinflammatory cytokine implicated under pathological conditions involving NMDA receptor activation, including the AIDS dementia complex (HAD). No information is available on the molecular mechanisms recruited by native interleukin-1␤ produced under this type of condition. Using a sandwich co-culture of primary hippocampal neurons and glia, we investigated whether native interleukin-1␤ released by HIV-gp120-activated glia (i) affects NMDAR functions and (ii) the relevance on neuronal spine density and survival, two specific traits of HAD. Increased phosphorylation of NR2B Tyr-1472 was observed after 24 h of exposure of neurons to 600 pM gp120. This effect occurred only when neurons were treated in the presence of glial cells and was abolished by the interleukin-1 receptor antagonist (IL-1ra). Gp120-induced phosphorylation of NR2B resulted in a sustained elevation of intracellular Ca 2؉ in neurons and in a significant increase of NR2B binding to PSD95. Increased intracellular Ca2؉ was prevented by 10 M ifenprodil, that selectively inhibits receptors containing the NR2B, by interleukin-1ra and by Ca-pYEEIE, a Src family SH2 inhibitor peptide. These last two inhibitors, prevented also NR2B binding to PSD95. Finally, gp120 reduced by 35% of the total PSD95 positive spine density after 48 h of treatment and induced by 30% of the neuronal death. Again, both of these effects were blocked by Ca-pYEEIE. Altogether, our data show that gp120 releasing interleukin-1␤ from glia increases tyrosine phosphorylation of NMDAR. Thus, tyrosine phosphorylation may contribute to the sensitization of the receptor increasing its function and synaptic localization. Both of these effects are relevant for neurodegeneration. Interleukin-1␤ (IL-1␤)3 has been proposed as a novel neuromodulator involved in the communication between glia and neurons (1-4), opening up new perspective in the current view of brain behavior. This cytokine, locally produced by glial cells as a consequence of CNS diseases and/or in response to neuronal activities (4), exerts a profound impact on neuronal functionality through a specific receptor. So far, IL-1␤ has been implicated in the exacerbation of neuronal damage caused by excitotoxic, ischemic, traumatic brain injury (5, 6), and viral infection (AIDS dementia complex: HAD) (7-9), in seizures (10) as well as in physiological events such as long-term potentiation (11, 12), sleep (13), memory consolidation (14, 15), and pain (16). Although IL-1␤ may offer exciting potential in the discovery of novel targets to modulate brain behavior, the biochemical pathways specifically recruited in neurons by this cytokine have not been explored in detail.Recombinant IL-1␤ potentiates calcium response and neuronal death achieved through NMDA receptor activation in primary hippocampal neurons by increasing phosphorylation of NR2B tyrosine 1472 (17). Tyrosine phosphorylation of NR2 subunits has been involved in NMDAR channel gating, protection of NR2 subunits against degradation by calpain, assembly with sig...

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Section: Discussionsupporting

confidence: 58%

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Viviani¹,

Gardoni²,

Bartesaghi

et al. 2006

Journal of Biological Chemistry

108

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“…Numerous lines of evidence suggest that extracellular proinflammatory cytokines and cellular toxins can induce neuronal apoptosis (Gabuzda et al, 1986;Gendelman et al, 1994;Shi et al, 1998;New et al, 1998;Bagetta et al, 1999;Holden et al, 1999;Zheng et al, 1999;Park et al, 2001;Takahashi et al, 1996). Furthermore, several studies suggest that HIV-1 Tat and gp120 interact with neuronally-expressed receptors to activate multiple pro-apoptotic signaling cascades in neurons Moore et al, 1997;New et al, 1997;Shi et al, 1998;Piller et al, 1999;Bonavia et al, 2001;Corasaniti et al, 2001;Haughey et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

“…Apoptotic changes are seen with HIVE in both neurons and nonneuronal cells (Ramirez et al, 2001;Bonavia et al, 2001;Corasaniti et al, 2001;AdleBiassette et al, 1995;Gelbard et al, 1995;Petito and Roberts, 1995;Shi et al, 1996;Kaul et al, 2001;Shi et al, 1998;Park et al, 2001). HIV-1 is neurotoxic by inducing inflammation and through the direct release of toxic viral proteins such as Nef, Vpr, gp120 and Tat (Haughey et al, 2001;Brenneman et al, 1988;Dreyer et al, 1990;Adamson et al, 1996;New et al, 1997;Kruman et al, 1998;Yeung et al, 1998;Huang and Bond, 2000;Trillo-Pazos et al, 2000;Nath, 2002). The neurotoxicity of gp120 has been demonstrated both in primary human neuronal cultures (Lannuzel et al, 1997;Yeung et al, 1995) and in transgenic mice (Toggas et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

et al. 2004

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“…49 Tat potentiates excitatory amino-acid (glutamate and NMDA) triggered calcium flux and neurotoxicity in cultured neurons. 147 Subtoxic concentrations of Tat combined with subtoxic concentrations of glutamate caused neuronal cell death. NMDA receptors play an important role in the neurotoxicities of both gp120 and Tat, which may explain the apparent efficacy of the noncompetitive NMDA receptor antagonist memantine in the treatment of HIV dementia patients.…”

Section: Excitotoxicity and Cellular Calcium Overloadmentioning

confidence: 99%

Cell death in HIV dementia

2005

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Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/ or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

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HIV‐1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity

Cited by 242 publications

References 63 publications

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

Cell death in HIV dementia

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