Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD

Han, Ki-Hoon; Kim, Myoung-Hwan; Seeburg, Daniel P.; Seo, Jinsoo; Verpelli, Chiara; Han, Seungnam; Chung, Hye Sun; Ko, Jaewon; Lee, Hyun Woo; Kim, Karam; Heo, Won Do; Meyer, Tobias; Kim, Hyun; Sala, Carlo; Choi, Se‐Young; Sheng, Morgan; Kim, Eunjoon

doi:10.1371/journal.pbio.1000187

Cited by 59 publications

(66 citation statements)

References 56 publications

(66 reference statements)

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“…LTD is impaired by RNAi knockdown or genetic disruption of PSD-95 in mice, and it can be enhanced by PSD-95 overexpression (Migaud et al 1998;Beique and Andrade 2003;Stein et al 2003;Ehrlich et al 2007;Carlisle et al 2008;Xu et al 2008). Activity-dependent dephosphorylation of PSD-95 (leading to destabilization of PSD-95 in the PSD), and PSD-95-mediated interactions with key signaling proteins (such as AKAP79/150 and protein phosphatases), may underlie the importance of PSD-95 in LTD Xu et al 2008;Bhattacharyya et al 2009;Han et al 2009). …”

Section: Psd-95mentioning

confidence: 99%

The Postsynaptic Organization of Synapses

Sheng¹,

Kim²

2011

Cold Spring Harbor Perspectives in Biology

474

426

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The postsynaptic side of the synapse is specialized to receive the neurotransmitter signal released from the presynaptic terminal and transduce it into electrical and biochemical changes in the postsynaptic cell. The cardinal functional components of the postsynaptic specialization of excitatory and inhibitory synapses are the ionotropic receptors (ligandgated channels) for glutamate and g-aminobutyric acid (GABA), respectively. These receptor channels are concentrated at the postsynaptic membrane and embedded in a dense and rich protein network comprised of anchoring and scaffolding molecules, signaling enzymes, cytoskeletal components, as well as other membrane proteins. Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization. The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness. E xcitatory synapses on principal neurons of mammalian brain occur mainly on tiny protrusions called dendritic spines (Bourne and Harris 2008). In contrast, inhibitory synapses are formed on the shaft of dendrites, or on cell bodies and axon initial segments. The postsynaptic side of excitatory synapses differs from inhibitory synapses not only in their content of neurotransmitter receptors but also in their morphology and molecular composition and organization. In part because of their greater abundance and distinctive structure, much more is known about the postsynaptic organization of central excitatory (glutamatergic) synapses. THE POSTSYNAPTIC DENSITY OF EXCITATORY SYNAPSESExcitatory synapses are characterized by a morphological and functional specialization of the postsynaptic membrane called the postsynaptic density (PSD), which is usually located at the tip of the dendritic spine. The PSD contains the glutamate receptors that are activated by the glutamate neurotransmitter released from the presynaptic terminal, as well as a host of associated signaling and structural molecules. A set of abundant scaffold proteins holds together the PSD by binding to the glutamate receptors, other postsynaptic receptors and adhesion

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Section: Psd-95mentioning

confidence: 99%

The Postsynaptic Organization of Synapses

Sheng¹,

Kim²

2011

Cold Spring Harbor Perspectives in Biology

474

426

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“…2C). 77 Surprisingly, Ral activation downstream of N-methyl-D-aspartate receptor (NMDAR) stimulation leads to removal of AMPARs from the cell surface. 78 Indeed, Ral is a bi-directional regulator of membrane traffic. When associated with the exocyst complex, Ral mediates the polarized delivery of vesicles toward the plasma membrane.…”

Section: The Role Of Small Gtpases and Recycling Endosomes In Neuronamentioning

confidence: 99%

“…During NMDAR-LTD, Ca 2C influx leads to Ral activation and recruitment of RalBP1 to spines. 78 NMDAR stimulation simultaneously activates a phosphatase called PP1, which dephosphorylates RalBP1, allowing its association with the scaffolding protein PSD-95. The close proximity of the AMPARs in complex with PSD-95 and endocytic proteins bound to RalBP1 initiates the internalization of AMPARs, a critical step preceding NMDAR-LTD.…”

Section: The Role Of Small Gtpases and Recycling Endosomes In Neuronamentioning

confidence: 99%

“…In further support of these observations, NMDAR-LTD is severely deficient in a RalBP1-KO mouse. 78 Interestingly, upon incorporation in endocytic sites, RalBP1 binds the endocytic adaptor epsin; and this interaction leads to its GAP-activity suppression. 79 This observation, along with the involvement of the RE and the exocyst, further expand the similarities with the cases of Bem3/Ocrl1.…”

Section: The Role Of Small Gtpases and Recycling Endosomes In Neuronamentioning

confidence: 99%

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RhoGTPase-binding proteins, the exocyst complex and polarized vesicle trafficking

2014

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“…mRNA and protein analysis demonstrated that REPS2 is predominantly expressed in the central nervous system as compared to other tissues (33,40), being particularly enriched in neuronal populations (33,49). REPS2 has been shown to regulate glutamate receptor endocytosis (33), but no further studies have addressed its role in neuronal function. REPS2 also regulates cell death pathways.…”

Section: Grx1 and S-glutathionylation In Pdreactive Species (Protein mentioning

confidence: 99%

Glutaredoxin 1 Protects Dopaminergic Cells by Increased Protein Glutathionylation in Experimental Parkinson's Disease

Rodríguez-Rocha

Garcia

Zavala-Flores

et al. 2012

Antioxidants & Redox Signaling

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Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knockdown sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.

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Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD

Abstract: A two step mechanism was identified that regulates receptor endocytosis during the development of long-term depression (LTD), a long-lasting decrease in synaptic transmission.

Cited by 59 publications

References 56 publications

The Postsynaptic Organization of Synapses

The Postsynaptic Organization of Synapses

RhoGTPase-binding proteins, the exocyst complex and polarized vesicle trafficking

Glutaredoxin 1 Protects Dopaminergic Cells by Increased Protein Glutathionylation in Experimental Parkinson's Disease

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