Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715000285 |
| _version_ | 1831806090670505984 |
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| author | Jocelyn Widagdo Ye Jin Chai Margreet C. Ridder Yu Qian Chau Richard C. Johnson Pankaj Sah Richard L. Huganir Victor Anggono |
| author_facet | Jocelyn Widagdo Ye Jin Chai Margreet C. Ridder Yu Qian Chau Richard C. Johnson Pankaj Sah Richard L. Huganir Victor Anggono |
| author_sort | Jocelyn Widagdo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T19:36:02Z |
| format | Article |
| id | doaj.art-58f93ae5adae47d188584b28a26bb7eb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T19:36:02Z |
| publishDate | 2015-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-58f93ae5adae47d188584b28a26bb7eb2022-12-21T18:14:57ZengElsevierCell Reports2211-12472015-02-0110578379510.1016/j.celrep.2015.01.015Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and DegradationJocelyn Widagdo0Ye Jin Chai1Margreet C. Ridder2Yu Qian Chau3Richard C. Johnson4Pankaj Sah5Richard L. Huganir6Victor Anggono7Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaQueensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaQueensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaQueensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAQueensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAQueensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, AustraliaAMPA 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.http://www.sciencedirect.com/science/article/pii/S2211124715000285 |
| spellingShingle | Jocelyn Widagdo Ye Jin Chai Margreet C. Ridder Yu Qian Chau Richard C. Johnson Pankaj Sah Richard L. Huganir Victor Anggono Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation Cell Reports |
| title | Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation |
| title_full | Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation |
| title_fullStr | Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation |
| title_full_unstemmed | Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation |
| title_short | Activity-Dependent Ubiquitination of GluA1 and GluA2 Regulates AMPA Receptor Intracellular Sorting and Degradation |
| title_sort | activity dependent ubiquitination of glua1 and glua2 regulates ampa receptor intracellular sorting and degradation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715000285 |
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