Abstract

Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.

Highlights

  • Ras-GRF1 and Ras-GRF2 are similar exchange factors with different functions in synaptic plasticity

  • Instead we developed an in vivo assay where GRF1, GRF2, and any mutant forms of them are tested for their ability to reconstitute TBS-LTP, low frequency stimulation-induced LTD (LFS-LTD), or high frequency stimulation-induced LTP (HFS-LTP) in double Grf1/Grf2 knockout (DBKO) mice that display none of these forms of synaptic plasticity

  • It reveals which of the six functional domains shared by GRF1 and GRF2 are most important for their ability to mediate different forms of synaptic plasticity induced by either NMDA or CP-AMPA glutamate receptors

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Summary

Background

Ras-GRF1 and Ras-GRF2 are similar exchange factors with different functions in synaptic plasticity. Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. They regulate different forms of synaptic plasticity. They both contain Rac-activating Dbl (DH) domains followed by PH domains, C-terminal Ras exchange motifs (REM), and Ras-activating CDC25 domains Despite these similarities, GRF1 and GRF2 display distinctly different roles in synaptic plasticity in the CA1 hippocampus.

The abbreviations used are
EXPERIMENTAL PROCEDURES
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