| Annotated protein: | Rap guanine nucleotide exchange factor 4 (Exchange factor directly activated by cAMP 2) (Exchange protein directly activated by cAMP 2) (EPAC 2) (cAMP-regulated guanine nucleotide exchange factor II) (cAMP-GEFII). Gene symbol: RAPGEF4. Taxonomy: Rattus norvegicus (Rat). Uniprot ID: Q9Z1C7 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ RAPGEF4 |
| Ontology domain: | Cellular Component |
| SynGO term: | presynapse (GO:0098793) |
| Synapse type(s): | cerebral cortex, glutamatergic |
| Annotated paper: | Woolfrey KM, et al. "Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines" Nat Neurosci. 2009 Oct;12(10):1275-84 PMID:19734897 |
| Figure(s): | Figure 1, 2, 4 |
| Annotation description: | Figure 1: immunofluorescence staining of endogenous Epac2 (aka. cAMP-GEFII, gene RAPGEF4) in cultured cortical pyramidal neurons showed partial co-localization with presynaptic marker Bassoon (BSN) and postsynaptic marker PSD95 (DLG4). While most of the manuscript describes postsynaptic functions of Epac2, various assays seemed to corroborate additional localization to the presynapse that was observed in Figure 1. Figure 2: "To determine whether 8-CPT affects the morphology of presynaptic terminals, we visualized presynaptic active zones with an antibody to bassoon. Epac2 activation significantly reduced the extent of presynaptic overlap with spines, as revealed by quantification of the intensity of bassoon immunofluorescence overlapping with individual spines (P < 0.001; Supplementary Fig. 7), suggesting that pre-postsynaptic apposition was reduced and synapses were weaker. These effects on spine/bassoon overlap were occluded by Epac2 RNAi (Supplementary Fig. 7). Incubation with 8-CPT also caused a reduction in bassoon-immunoreactive cluster size (Supplementary Fig. 7), indicating a potential presynaptic effect." Figure 4: "Incubation of neurons with 8-CPT (50 μM, 1 h) resulted in a robust reduction in the mean amplitudes (34%) and frequency (59%) of AMPAR-mediated mEPSCs (P < 0.05; Fig. 4a), resulting in a shift in the distribution of mEPSC amplitudes toward smaller values. RNAi knockdown of Epac2 in postsynaptic neurons prevented 8-CPT from reducing the basal mean mEPSC amplitude (Fig. 4a), confirming the Epac2 specificity of the 8-CPT effect. RNAi expression did not increase the mean amplitude or frequency of AMPAR mEPSCs, consistent with our immunostaining data. Notably, the presence of RNAi in the postsynaptic cell did not affect the 8-CPT-dependent reduction in mEPSC frequency (P < 0.01), suggesting that these effects were caused by activation of presynaptic Epac2, dissociating the pre- and postsynaptic actions of Epac2." |
| Evidence tracking, Biological System: | Cultured neurons |
| Evidence tracking, Protein Targeting: | Antibody (detection) Antagonist / agonist |
| Evidence tracking, Experiment Assay: | Confocal Whole-cell patch clamp |
| Annotator(s): | Frank Koopmans (ORCID:0000-0002-4973-5732) Guus Smit (ORCID:0000-0002-2286-1587) Matthijs Verhage (ORCID:0000-0002-2514-0216) |
| Lab: | Department of Functional Genomics, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands |
| Additional literature: | RAPGEF4 (aka. Epac2 / cAMP-GEFII) can interact with presynaptic active zone protein Piccolo (PCLO) @ PMID:12401793 "These data suggest that cAMP elevation uses an Epac2-dependent pathway to promote transmitter release, and that Epac2 is required to maintain the readily releasable pool at MF synapses in the hippocampus." @ PMID:25904804 |
| SynGO annotation ID: | 5457 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |