RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission

Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14462-7. doi: 10.1073/pnas.1304340110. Epub 2013 Aug 12.

Abstract

Dendritic spines are the primary sites of excitatory synaptic transmission in the vertebrate brain, and the morphology of these actin-rich structures correlates with synaptic function. Here we demonstrate a unique method for inducing spine enlargement and synaptic potentiation in dispersed hippocampal neurons, and use this technique to identify a coordinator of these processes; Ras-specific guanine nucleotide releasing factor 2 (RasGRF2). RasGRF2 is a dual Ras/Rac guanine nucleotide exchange factor (GEF) that is known to be necessary for long-term potentiation in situ. Contrary to the prevailing assumption, we find RasGRF2's Rac-GEF activity to be essential for synaptic potentiation by using a molecular replacement strategy designed to dissociate Rac- from Ras-GEF activities. Furthermore, we demonstrate that Rac1 activity itself is sufficient to rapidly modulate postsynaptic strength by using a photoactivatable derivative of this small GTPase. Because Rac1 is a major actin regulator, our results support a model where the initial phase of long-term potentiation is driven by the cytoskeleton.

Keywords: AMPA receptor; LTP; Rho GTPase; synaptic plasticity.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cells, Cultured
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synaptic Transmission*
  • ras Guanine Nucleotide Exchange Factors / metabolism*

Substances

  • Guanine Nucleotide Exchange Factors
  • RASGRF2 protein, human
  • Receptors, N-Methyl-D-Aspartate
  • ras Guanine Nucleotide Exchange Factors
  • Calcium