| Annotated protein: | Gamma-aminobutyric acid receptor subunit alpha-4 (GABA(A) receptor subunit alpha-4). Gene symbol: GABRA4. Taxonomy: Rattus norvegicus (Rat). Uniprot ID: P28471 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ GABRA4 |
| Ontology domain: | Biological Process |
| SynGO term: | transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315) |
| Synapse type(s): | hippocampus, GABAergic |
| Annotated paper: | Liang J, et al. "Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors" J Neurosci. 2006 Feb 8;26(6):1749-58 PMID:16467523 |
| Figure(s): | Fig.4, 5 |
| Annotation description: | Fig.4: "Altered synaptic and extrasynaptic sensitivity to THIP and LaCl3 after CIE treatment." - "In recombinant receptor studies, these compounds were shown to have a particularly high affinity for the α4β3δ GABAAR subunit combination (Brown et al., 2002) ... Application of THIP (1 μm) produced large increases in Ihold and a small but significant prolongation of the mIPSC decay time in DG cells from saline-treated rats. Subsequent addition of LaCl3 (100 μm) produced a significant reduction in the THIP-induced tonic current, without affecting mIPSC decay (Fig. 4A,B)." Fig.5: "Altered synaptic and extrasynaptic sensitivity to Ro15-4513 after CIE treatment." - "we examined the effect of CIE treatment on responses to Ro15-4513, a partial inverse agonist at the benzodiazepine site of α1- and α2-containing GABAARs, which was also shown to bind with high affinity at α4-containing GABAARs (Knoflach et al., 1996). Importantly, Ro15-4513 has agonist activity at α4β3γ2 GABAARs but does not modulate α4β3δ GABAARs (Brown et al., 2002). In DG cells from saline-treated rats, Ro15-4513 (0.3 μm) slightly but significantly potentiated both mIPSCs and Ihold (Fig. 5A,B). After CIE treatment, mIPSC potentiation by Ro15-4513 was markedly increased, whereas Ihold was now inhibited by the drug." Abstract: "Electrophysiological assays demonstrated a CIE-induced long-term loss of extrasynaptic GABAA receptor (GABAAR) responsiveness and a gain of synaptic GABAAR responsiveness of CA1 pyramidal and dentate granule neurons to EtOH that we were able to relate to behavioral effects. After CIE treatment, the α4 subunit-preferring GABAAR ligands 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, La3+, and Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5α][1,4]benzodiazepine-3-carboxylate) exerted decreased effects on extrasynaptic currents but had increased effects on synaptic currents. Electron microscopy revealed an increase in central synaptic localization of α4 but not δ subunits within GABAergic synapses on the dentate granule cells of CIE rats." - In short, alpha4 containing GABAaRs move from the extrasynaptic membrane into the synaptic specialization membrane after chronic intermittent ethanol (CIE) treatment. |
| Evidence tracking, Biological System: | Intact tissue |
| Evidence tracking, Protein Targeting: | Antagonist / agonist |
| Evidence tracking, Experiment Assay: | Whole-cell patch clamp |
| Annotator(s): | Pim van Nierop (ORCID:0000-0003-0593-3443) 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 |
| SynGO annotation ID: | 2084 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |