The PSD95–nNOS interface

Cao, Jiong; Viholainen, Jenni I.; Dart, Caroline; Warwick, Helen K.; Leyland, Mark L.; Courtney, Michael J.

doi:10.1083/jcb.200407024

Cited by 130 publications

(49 citation statements)

References 46 publications

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“…The exact mechanism of NO-induced neuronal apoptosis in our system has not been determined. NO activates the p38 apoptotic pathway in the context of glutamateinduced neuronal apoptosis (37) and may be contributing to apoptotic signaling in our system through this mechanism. Alternatively, high NO production leads to the generation of free radicals and mitochondrial damage (18), which also may be occurring in response to tat.…”

Section: Discussionmentioning

confidence: 99%

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

Eugenín¹,

King²,

Nath

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

186

222

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HIV infection of the central nervous system can result in neurologic dysfunction with devastating consequences in AIDS patients. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence that HIV can infect neurons. Here we show that the HIV-encoded protein tat triggers formation of a macromolecular complex involving the low-density lipoprotein receptor-related protein (LRP), postsynaptic density protein-95 (PSD-95), N-methyl-D-aspartic acid (NMDA) receptors, and neuronal nitric oxide synthase (nNOS) at the neuronal plasma membrane, and that this complex leads to apoptosis in neurons negative as well as positive for NMDA receptors and also in astrocytes. Blockade of LRPmediated tat uptake, NMDA receptor activation, or neuronal nitric oxide synthase significantly reduces ensuing neuronal apoptosis, suggesting that formation of this complex is an early step in tat toxicity. We also show that the inflammatory chemokine, CCL2, protects against tat toxicity and inhibits formation of the complex. These findings implicate the complex in HIV-induced neuronal apoptosis and suggest therapeutic targets for intervention in the pathogenesis of NeuroAIDS.glutamate ͉ dementia ͉ HIV-1 ͉ NeuroAIDS ͉ excitotoxicity H IV enters the CNS early after infection. Viral persistence within the CNS can produce cognitive impairment, HIV encephalitis, and, in some cases, dementia. NeuroAIDS is characterized by neuronal damage and loss and cognitive and motor deficits and can have devastating consequences in a significant number of individuals with AIDS. As HIV-infected individuals live longer on antiretroviral therapy, the prevalence of cognitive impairment is increasing, and the study of the pathogenesis of NeuroAIDS becomes even more critical (1, 2).Although HIV infection of the CNS causes neuronal cell damage and loss, the virus cannot directly infect neurons. Rather, HIV-associated damage is thought to be due to an indirect mechanism whereby virally infected, as well as uninfected, cells elaborate neurotoxins. Candidate toxins include cytokines, glutamate, and virally encoded proteins such as the HIV transactivator protein, tat (3). Tat potentiates glutamateinduced excitotoxicity (4, 5) and promotes neuronal apoptosis (6-8). Antagonists of the N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) protect against tat-induced apoptosis (5, 7), implicating NMDARs in this process.The low-density lipoprotein receptor-related protein (LRP) is expressed by many cells in the CNS, including neurons and astrocytes (9, 10). LRP is a receptor for at least 16 endogenous ligands and also for the viral protein tat, and mediates uptake of these ligands into endosomes in various cells, including neurons (9). Tat and some other LRP ligands can activate NMDARs and mediate calcium signaling in neurons (4,11,12). Tat, in contrast to other LRP ligands, escapes from the endosomal/lysosomal compartment (9) and, by mechanisms still poorly known, induces apoptosis in both neurons and astrocytes.This study was undertaken to examine mechanisms by...

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Section: Discussionmentioning

confidence: 99%

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

Eugenín¹,

King²,

Nath

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

186

222

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“…Each single PDZ domain was cloned into the pcDNA 3.1 zeo (ϩ) vector (Invitrogen), bearing a 3ϫ FLAG sequence at its N terminus. The corresponding nucleotide sequences (rat) are as follows: PDZI (nucleotides 178 -465), PDZII (nucleotides 463-747), and PDZIII (nucleotides 904 -1206) (19). Additionally, a GW1-CMV-vector bearing the full-length PSD95 protein (a kind gift of Dr. Morgan Sheng) (20) was transfected.…”

Section: Methodsmentioning

confidence: 99%

The Functional Role of the Second NPXY Motif of the LRP1 β-Chain in Tissue-type Plasminogen Activator-mediated Activation of N-Methyl-D-aspartate Receptors

Martin

Kuhlmann

Trossbach

et al. 2008

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of NMDA receptor calcium influx with MK-801 resulted in dramatic reduction of tPA-mediated downstream signaling. This indicates a functional interaction between the two receptors, since both experimental approaches resulted in strongly reduced calcium influx and Erk1/2 phosphorylation. Additionally, we were able to inhibit Erk1/2 activation by competing for the LRP1 C-terminal binding motif with a truncated PSD95 construct resembling its PDZ III domain. Furthermore, we identified the distal NPXY amino acid motif in the C terminus of LRP1 as the crucial element for LRP1-NMDA receptor interaction via the adaptor protein PSD95. These results provide new insights into the mechanism of a tPA-induced, LRP1-mediated gating mechanism for NMDA receptors.LRP1 (low density lipoprotein receptor-related protein) is a member of the low density lipoprotein receptor gene family with its highest expression in liver and brain. Following its synthesis in the endoplasmic reticulum as a 600-kDa type I transmembrane glycoprotein, LRP1 is cleaved in the Golgi compartment by furin, producing two subunits, 515 and 85 kDa in size. These two subunits remain noncovalently associated during their transport to the cell surface (1). Via a receptor-recycling pathway, LRP1 is responsible for the endocytosis of more than 30 different extracellular ligands (2, 3). In neurons, where it is highly expressed and predominantly localized in neuronal cell bodies and dendritic processes (4), LRP1 is a major receptor for apoE/lipoprotein-containing particles and tissue-type plasminogen activator (tPA) 2 (5). In addition to its role in endocytosis of various ligands, LRP1 has been implicated to play a crucial role in cell signaling. The observation that the LRP1 C terminus undergoes rapid tyrosine phosphorylation after tPA binding corroborates its function as a signal transmitter (6). Several adaptor proteins can bind to the LRP1 tail, some of which seem to play a role in neuronal calcium, platelet-derived growth factor, or MAPK signaling (7-9). Beyond its known function of lipid uptake, LRP1 has also been attributed to be the mediator of an LTP-enhancing effect of exogenously added tPA in hippocampal slices from tPA-deficient mice (5). Further evidence supporting the hypothesis of an involvement in synaptic plasticity results from neuron-specific LRP1 knock-out mice, which...

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“…Thus, complete ablation of PSD95 with antisense and dissociation of the entire PSD95 molecule from the NMDAR with PDZ 1-2 decoy constructs are neuroprotective in ischemia models [58,63] interface is a target for designing neuroprotective drugs [64] .…”

Section: Adapter Proteins Of Nnosmentioning

confidence: 99%

“…NMDARs form large and dynamic signaling complexes in the postsynaptic membrane, mainly through the interaction of their intracellular NR2 C-terminus with PSD95 [125] , a scaffolding protein that binds both NMDARs and nNOS at excitatory synapses and assembles them into a macromolecular signaling complex [63,64] . PSD95 is an important signaling enzyme in the CNS.…”

Section: Nnos and Neuronal Deathmentioning

confidence: 99%

Research progress on neurobiology of neuronal nitric oxide synthase

Luo

Zhu

2011

Neurosci. Bull.

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Neuronal nitric oxide synthase (nNOS) is mainly expressed in neurons, to some extent in astrocytes and neuronal stem cells. The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS, including nNOS-α, nNOS-β, nNOS-µ, nNOS-γ and nNOS-2. Monomer of nNOS is inactive, and dimer is the active form. Dimerization requires tetrahydrobiopterin (BH4), heme and L-arginine binding. Regulation of nNOS expression relies largely on cAMP response element-binding protein (CREB) activity, and nNOS activity is regulated by heat shock protein 90 (HSP90)/HSP70, calmodulin (CaM), phosphorylation and dephosphorylation at Ser847 and Ser1412, and the protein inhibitor of nNOS (PIN). There are primarily 9 nNOS-interacting proteins, including post-synaptic density protein 95 (PSD95), clathrin assembly lymphoid leukemia (CALM), calcium/calmodulin-dependent protein kinase II alpha (CAMKIIA), Disks large homolog 4 (DLG4), DLG2, 6-phosphofructokinase, muscle type (PFK-M), carboxy-terminal PDZ ligand of nNOS (CAPON) protein, syntrophin and dynein light chain (LC). Among them, PSD95, CAPON and PFK-M are important nNOS adapter proteins in neurons. The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death. nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states, and negatively regulates neurogenesis under physiological and pathological conditions.

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The PSD95–nNOS interface

Cited by 130 publications

References 46 publications

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

HIV-tat induces formation of an LRP–PSD-95– NMDAR–nNOS complex that promotes apoptosis in neurons and astrocytes

The Functional Role of the Second NPXY Motif of the LRP1 β-Chain in Tissue-type Plasminogen Activator-mediated Activation of N-Methyl-D-aspartate Receptors

Research progress on neurobiology of neuronal nitric oxide synthase

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