AKAP150 Palmitoylation Regulates Synaptic Incorporation of Ca 2+-Permeable AMPA Receptors to Control LTP

Cell Rep. 2018 Oct 23;25(4):974-987.e4. doi: 10.1016/j.celrep.2018.09.085.

Abstract

Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits contribute to multiple forms of synaptic plasticity, including long-term potentiation (LTP), but mechanisms regulating CP-AMPARs are poorly understood. A-kinase anchoring protein (AKAP) 150 scaffolds kinases and phosphatases to regulate GluA1 phosphorylation and trafficking, and trafficking of AKAP150 itself is modulated by palmitoylation on two Cys residues. Here, we developed a palmitoylation-deficient knockin mouse to show that AKAP150 palmitoylation regulates CP-AMPAR incorporation at hippocampal synapses. Using biochemical, super-resolution imaging, and electrophysiological approaches, we found that palmitoylation promotes AKAP150 localization to recycling endosomes and the postsynaptic density (PSD) to limit CP-AMPAR basal synaptic incorporation. In addition, we found that AKAP150 palmitoylation is required for LTP induced by weaker stimulation that recruits CP-AMPARs to synapses but not stronger stimulation that recruits GluA2-containing AMPARs. Thus, AKAP150 palmitoylation controls its subcellular localization to maintain proper basal and activity-dependent regulation of synaptic AMPAR subunit composition.

Keywords: AKAP; LTD; LTP; PKA; PSD; calcineurin; calcium-permeable AMPA receptor; palmityolation.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cell Membrane Permeability*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dendritic Spines / metabolism
  • Endosomes / metabolism
  • Lipoylation*
  • Long-Term Potentiation*
  • Mice, Inbred C57BL
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*
  • Synaptic Transmission

Substances

  • A Kinase Anchor Proteins
  • Akap5 protein, mouse
  • Receptors, AMPA
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium