Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD

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

doi:10.1371/journal.pbio.1000187

Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD

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

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

Abstract

Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)-dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.

Original language	English
Article number	e1000187
Journal	PLoS biology
Volume	7
Issue number	9
DOIs	https://doi.org/10.1371/journal.pbio.1000187
Publication status	Published - 2009
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Agricultural and Biological Sciences(all)

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title = "Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD",

abstract = "Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)-dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.",

author = "Kihoon Han and Kim, {Myoung Hwan} and Daniel Seeburg and Jinsoo Seo and Chiara Verpelli and Seungnam Han and Hye, {Sun Chung} and Jaewon Ko and Hyun, {Woo Lee} and Karam Kim and Won, {Do Heo} and Tobias Meyer and Hyun Kim and Carlo Sala and Choi, {Se Young} and Morgan Sheng and Eunjoon Kim",

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AU - Han, Kihoon

AU - Kim, Myoung Hwan

AU - Seeburg, Daniel

AU - Seo, Jinsoo

AU - Verpelli, Chiara

AU - Han, Seungnam

AU - Hye, Sun Chung

AU - Ko, Jaewon

AU - Hyun, Woo Lee

AU - Kim, Karam

AU - Won, Do Heo

AU - Meyer, Tobias

AU - Kim, Hyun

AU - Sala, Carlo

AU - Choi, Se Young

AU - Sheng, Morgan

AU - Kim, Eunjoon

PY - 2009

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AB - Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)-dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.

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Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD

Abstract

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