Subunit-Specific Augmentation of AMPA Receptor Ubiquitination by Phorbol Ester

Jocelyn Widagdo, Jun Wei Kerk, Sumasri Guntupalli, Richard L. Huganir, Victor Anggono

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Excitatory neurotransmission relies on the precise targeting of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors to the neuronal plasma membrane. Activity-dependent ubiquitination of AMPA receptor (AMPAR) subunits sorts internalised receptors to late endosomes for degradation, which ultimately determines the number of AMPARs on neuronal membrane. Our recent study has demonstrated a functional cross-talk between the phosphorylation and ubiquitination of the GluA1 subunit in mammalian central neurons. However, the existence of such a cross modulation for the GluA2 subunit remains unknown. Here, we have shown that bicuculline induced GluA2 ubiquitination on the same lysine residues (Lys-870 and Lys-882) in the C-terminal as those elicited by the AMPA treatment. Interestingly, bicuculline-induced ubiquitination was markedly enhanced by the phospho-mimetic GluA2 S880E mutant. Pharmacological activation of protein kinase C (PKC) by phorbol ester, which mediates the phosphorylation of GluA2 at Ser-880, augmented bicuculline-induced ubiquitination of GluA2 in cultured neurons. This effect was specific for the GluA2 subunit because phorbol ester did not alter the level of GluA1 ubiquitination. However, phorbol ester-induced enhancement of GluA2 ubiquitination did not require Ser-880 phosphorylation. This suggests that pseudo-phosphorylation of Ser-880 is sufficient but is not necessary for the augmentation of bicuculline-induced GluA2 ubiquitination. Collectively, these data provide the first demonstration of subunit-specific modulation of AMPAR ubiquitination by the PKC-dependent signalling pathway in mammalian central neurons.

Original languageEnglish (US)
Pages (from-to)1213-1222
Number of pages10
JournalCellular and molecular neurobiology
Issue number7
StatePublished - Oct 1 2020


  • AMPA receptors
  • Phorbol ester
  • Phosphorylation
  • Protein kinase C
  • Ubiquitination

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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