PIKE-mediated PI3-kinase activity is required for AMPA receptor surface expression

EMBO J. 2011 Aug 16;30(20):4274-86. doi: 10.1038/emboj.2011.281.

Abstract

AMPAR (α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor) is an ion channel involved in the formation of synaptic plasticity. However, the molecular mechanism that couples plasticity stimuli to the trafficking of postsynaptic AMPAR remains poorly understood. Here, we show that PIKE (phosphoinositide 3-kinase enhancer) GTPases regulate neuronal AMPAR activity by promoting GluA2/GRIP1 association. PIKE-L directly interacts with both GluA2 and GRIP1 and forms a tertiary complex upon glycine-induced NMDA receptor activation. PIKE-L is also essential for glycine-induced GluA2-associated PI3K activation. Genetic ablation of PIKE (PIKE(-/-)) in neurons suppresses GluA2-associated PI3K activation, therefore inhibiting the subsequent surface expression of GluA2 and the formation of long-term potentiation. Our findings suggest that PIKE-L is a critical factor in controlling synaptic AMPAR insertion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Brain / metabolism
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Glycine / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Long-Term Potentiation
  • Mice
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rats
  • Receptors, AMPA / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GRIP1 protein, human
  • GTPase-Activating Proteins
  • Grip1 protein, mouse
  • Grip1 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • AGAP2 protein, human
  • Agap2 protein, rat
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • PIKE protein, mouse
  • Monomeric GTP-Binding Proteins
  • Glycine