Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD

J Biol Chem. 2015 Jun 26;290(26):16357-71. doi: 10.1074/jbc.M114.599399. Epub 2015 May 5.

Abstract

The fate of a memory, whether stored or forgotten, is determined by the ability of an active or tagged synapse to undergo changes in synaptic efficacy requiring protein synthesis of plasticity-related proteins. A synapse can be tagged, but without the "capture" of plasticity-related proteins, it will not undergo long lasting forms of plasticity (synaptic tagging and capture hypothesis). What the "tag" is and how plasticity-related proteins are captured at tagged synapses are unknown. Ca(2+)/calmodulin-dependent protein kinase II α (CaMKIIα) is critical in learning and memory and is synthesized locally in neuronal dendrites. The mechanistic (mammalian) target of rapamycin (mTOR) is a protein kinase that increases CaMKIIα protein expression; however, the mechanism and site of dendritic expression are unknown. Herein, we show that mTOR activity mediates the branch-specific expression of CaMKIIα, favoring one secondary, daughter branch over the other in a single neuron. mTOR inhibition decreased the dendritic levels of CaMKIIα protein and mRNA by shortening its poly(A) tail. Overexpression of the RNA-stabilizing protein HuD increased CaMKIIα protein levels and preserved its selective expression in one daughter branch over the other when mTOR was inhibited. Unexpectedly, deleting the third RNA recognition motif of HuD, the domain that binds the poly(A) tail, eliminated the branch-specific expression of CaMKIIα when mTOR was active. These results provide a model for one molecular mechanism that may underlie the synaptic tagging and capture hypothesis where mTOR is the tag, preventing deadenylation of CaMKIIα mRNA, whereas HuD captures and promotes its expression in a branch-specific manner.

Keywords: RNA-binding protein; dendritic branch; fluorescence; in situ hybridization; mRNA decay; mammalian target of rapamycin (mTOR); neuron; protein synthesis; synaptic tagging and capture; translational control.

Publication types

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

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Dendrites / enzymology
  • Dendrites / genetics
  • Dendrites / metabolism*
  • ELAV Proteins / genetics
  • ELAV Proteins / metabolism*
  • ELAV-Like Protein 4
  • Hippocampus / cytology
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Neurons / metabolism
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Rats
  • Synapses / enzymology
  • Synapses / genetics
  • Synapses / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • ELAV Proteins
  • ELAV-Like Protein 4
  • Elavl4 protein, rat
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, rat