SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway

Nat Neurosci. 2009 Aug;12(8):1011-9. doi: 10.1038/nn.2362. Epub 2009 Jul 20.

Abstract

Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Bodily Secretions / physiology
  • Cell Compartmentation / physiology
  • Cell Line
  • Cells, Cultured
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Golgi Apparatus / metabolism*
  • Golgi Apparatus / ultrastructure
  • Guanylate Kinases / metabolism*
  • Hippocampus / metabolism*
  • Hippocampus / ultrastructure
  • Humans
  • Kinesin / metabolism
  • Membrane Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Dlg1 protein, rat
  • KIF17 protein, mouse
  • Membrane Proteins
  • NR1 NMDA receptor
  • NR2B NMDA receptor
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • CASK kinases
  • Guanylate Kinases
  • Kinesin