title: Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation.
abstract: AMPA receptors (AMPARs) have recently been shown to undergo post-translational ubiquitination in mammalian neurons. However, the underlying molecular mechanisms are poorly understood and remain controversial. Here, we report that all four AMPAR subunits (GluA1-4) are rapidly ubiquitinated upon brief application of AMPA or bicuculline in cultured neurons. This process is Ca2+dependent and requires the activity of L-type voltage-gated Ca2+channels and Ca2+/calmodulin-dependent kinase II. The ubiquitination of all subunits occurs exclusively on AMPARs located on the plasma membrane post-endocytosis. The sites of ubiquitination were mapped to Lys-868 in GluA1 and Lys-870/Lys-882 in GluA2 C-terminals. Mutation of these lysines did not affect basal surface expression or AMPA-induced internalization of GluA1 and GluA2 subunits. Instead, it reduced the intracellular trafficking of AMPARs to the late endosomes and thus protein degradation. These data indicate that ubiquitination is an important regulatory signal for controlling AMPAR function, which may be crucial for synaptic plasticity.
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Jocelyn
authors: J
authors: Widagdo
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Ye Jin
authors: YJ
authors: Chai
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Margreet C
authors: MC
authors: Ridder
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Yu Qian
authors: YQ
authors: Chau
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Richard C
authors: RC
authors: Johnson
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Pankaj
authors: P
authors: Sah
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rhuganir@jhmi.edu.
authors: Richard L
authors: RL
authors: Huganir
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: v.anggono@uq.edu.au.
authors: Victor
authors: V
authors: Anggono