Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD.
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.
Han
Kihoon
K
National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Kim
Myoung-Hwan
MH
Seeburg
Daniel
D
Seo
Jinsoo
J
Verpelli
Chiara
C
Han
Seungnam
S
Chung
Hye Sun
HS
Ko
Jaewon
J
Lee
Hyun Woo
HW
Kim
Karam
K
Heo
Won Do
WD
Meyer
Tobias
T
Kim
Hyun
H
Sala
Carlo
C
Choi
Se-Young
SY
Sheng
Morgan
M
Kim
Eunjoon
E
D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004705:Endocytosis / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C490620:Ralbp1 protein, mouse; C094755:Ralbp1 protein, rat; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C492197:Rala protein, rat; D020725:ral GTP-Binding Proteins