Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing proteins and regulates AMPA receptor transmission

Gareth M. Thomas, Gavin R. Rumbaugh, Dana B. Harrar, Richard L. Huganir

Research output: Contribution to journalArticlepeer-review

Abstract

Extracellular signal-regulated kinase (ERK) signaling is important for neuronal synaptic plasticity. We report here that the protein kinase ribosomal S6 kinase (RSK)2, a downstream target of ERK, uses a C-terminal motif to bind several PDZ domain proteins in heterologous systems and in vivo. Different RSK isoforms display distinct specificities in their interactions with PDZ domain proteins. Mutation of the RSK2 PDZ ligand does not inhibit RSK2 activation in intact cells or phosphorylation of peptide substrates by RSK2 in vitro but greatly reduces RSK2 phosphorylation of PDZ domain proteins of the Shank family in heterologous cells. In primary neurons, NMDA receptor (NMDA-R) activation leads to ERK and RSK2 activation and RSK-dependent phosphorylation of transfected Shank3. RSK2-PDZ domain interactions are functionally important for synaptic transmission because neurons expressing kinase-dead RSK2 display a dramatic reduction in frequency of AMPA-type glutamate receptor-mediated miniature excitatory postsynaptic currents, an effect dependent on the PDZ ligand. These results suggest that binding of RSK2 to PDZ domain proteins and phosphorylation of these proteins or their binding partners regulates excitatory synaptic transmission.

Original languageEnglish (US)
Pages (from-to)15006-15011
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number42
DOIs
StatePublished - Oct 18 2005

Keywords

  • Extracellular signal-regulated kinase
  • Glutamate receptors
  • RAS
  • Synaptic plasticity

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing proteins and regulates AMPA receptor transmission'. Together they form a unique fingerprint.

Cite this