SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation

Neuron. 2004 Aug 19;43(4):563-74. doi: 10.1016/j.neuron.2004.08.003.

Abstract

The synapse contains densely localized and interacting proteins that enable it to adapt to changing inputs. We describe a Ca2+-sensitive protein complex involved in the regulation of AMPA receptor synaptic plasticity. The complex is comprised of MUPPI, a multi-PDZ domain-containing protein; SynGAP, a synaptic GTPase-activating protein; and the Ca2+/calmodulin-dependent kinase CaMKII. In synapses of hippocampal neurons, SynGAP and CaMKII are brought together by direct physical interaction with the PDZ domains of MUPP1, and in this complex, SynGAP is phosphorylated. Ca2+CaM binding to CaMKII dissociates it from the MUPP1 complex, and Ca2+ entering via the NMDAR drives the dephosphorylation of SynGAP. Specific peptide-induced SynGAP dissociation from the MUPP1-CaMKII complex results in SynGAP dephosphorylation accompanied by P38 MAPK inactivation, potentiation of synaptic AMPA responses, and an increase in the number of AMPAR-containing clusters in hippocampal neuron synapses. siRNA-mediated SynGAP knockdown confirmed these results. These data implicate SynGAP in NMDAR- and CaMKII-dependent regulation of AMPAR trafficking.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Line
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / physiology*
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Nerve Tissue Proteins / physiology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synapses / enzymology
  • Synapses / genetics
  • Synapses / physiology*
  • Synaptic Transmission / physiology*
  • Transfection
  • p38 Mitogen-Activated Protein Kinases
  • ras GTPase-Activating Proteins

Substances

  • Carrier Proteins
  • GTPase-Activating Proteins
  • Intracellular Signaling Peptides and Proteins
  • MPDZ protein, human
  • Mpdz protein, rat
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • SYNGAP1 protein, human
  • Syngap1 protein, rat
  • ras GTPase-Activating Proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases