SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression

Cell Rep. 2016 Sep 13;16(11):2901-2913. doi: 10.1016/j.celrep.2016.08.020.

Abstract

Short-term synaptic depression (STD) is a common form of activity-dependent plasticity observed widely in the nervous system. Few molecular pathways that control STD have been described, but the active zone (AZ) release apparatus provides a possible link between neuronal activity and plasticity. Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. A phosphomimetic CAST (S45D) mimics CAST deletion, which enhances STD by delaying reloading of the readily releasable pool (RRP), resulting in a pool size decrease. A phosphonegative CAST (S45A) inhibits STD and accelerates RRP reloading. Our results suggest that the CAST/SAD-B reaction serves as a brake on synaptic transmission by temporal calibration of activity and synaptic depression via RRP size regulation.

Keywords: phosphorylation; presynaptic active zone; short-term plasticity; sympathetic neuron; synaptic vesicle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / pharmacology
  • Cell Membrane / physiology
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism*
  • Endocytosis*
  • HEK293 Cells
  • Humans
  • Long-Term Potentiation*
  • Membrane Potentials / physiology
  • Mice, Transgenic
  • Neurons / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Superior Cervical Ganglion / cytology
  • Synaptic Vesicles / metabolism*

Substances

  • Cytoskeletal Proteins
  • Erc2 protein, mouse
  • Brsk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Calcium