Abstract
Author SummaryNeurons adapt over time in order to dampen their response to prolonged or particularly strong stimuli. This process, termed long-term depression (LTD), results in a long-lasting decrease in the efficiency of synaptic transmission. One extensively studied form of LTD requires the activation of a specific class of receptors known as NMDA glutamate receptors (NMDARs). A key molecular event initiated by NMDA receptor activation is the stimulation of protein phosphatases. Another key event is internalization via endocytosis of synaptic AMPA glutamate receptors (AMPARs). However, the mechanism by which protein dephosphorylation is coupled to AMPAR endocytosis has remained unclear. Here, we help to define this mechanism. We show that endocytic proteins, including RalBP1, are widely distributed in neurons under normal conditions. Upon NMDAR activation, the small GTPase RalA becomes activated and binds to RalBP1, resulting in the translocation of RalBP1 and RalBP1-associated endocytic proteins to synapses. At the same time, RalBP1 becomes dephosphorylated, which promotes its binding to the postsynaptic scaffold protein PSD-95, a protein that itself associates with AMPARs. This concerted recruitment of endocytic proteins to the vicinity of AMPARs results in AMPAR endocytosis. On the basis of our data, we propose a model in which dual binding of RalBP1 to both RalA and PSD-95 following RalBP1 dephosphorylation is essential for NMDAR-dependent AMPAR endocytosis during LTD.
Highlights
Long-term depression (LTD), a long-lasting activity-dependent decrease in synaptic strength, has been implicated in brain development, learning and memory, drug addiction, and mental retardation [1]
The clathrin adaptor complex AP2, which directly binds to AMPA receptor (AMPAR) and is required for NMDA receptor (NMDAR)-dependent AMPAR endocytosis and LTD [5,16], should be brought close to AMPARs in a tightly regulated manner, but little is known about the underlying mechanism
On the basis of our data, we propose a model in which dual binding of RalBP1 to both RalA and PSD-95 following RalBP1 dephosphorylation is essential for NMDAR-dependent AMPAR endocytosis during LTD
Summary
Long-term depression (LTD), a long-lasting activity-dependent decrease in synaptic strength, has been implicated in brain development, learning and memory, drug addiction, and mental retardation [1]. Little is known about the identity of key phosphatase substrates and, more importantly, how their dephosphorylation promotes AMPAR endocytosis during NMDAR-dependent LTD. NMDAR-dependent LTD and AMPAR endocytosis, including the GluR1 subunit of AMPARs [11,12,13], stargazin [14], and PSD95 [15]. Their dephosphorylation has not been clearly linked to the regulation of AMPAR endocytosis. The clathrin adaptor complex AP2, which directly binds to AMPARs and is required for NMDAR-dependent AMPAR endocytosis and LTD [5,16], should be brought close to AMPARs in a tightly regulated manner, but little is known about the underlying mechanism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
