Fig. 6: Allosteric modulators of GABAARs regulate spontaneous currents.
From: Structural determinants and regulation of spontaneous activity in GABAA receptors
a Recordings of various receptor isoforms exposed to the positive allosteric modulators THDOC (100 nM), allopregnanolone (AP, 100 nM) and propofol (1 μM). b Modulator-induced changes in holding current IMod were measured, before saturating GABA (500 μM) and PTX (100 μM) were applied. The IMod was added to the IPTX to calculate Ispont in the presence of the modulators (see Methods). Wild-type α4β3δ Ispont was potentiated by THDOC (***P = 4.7E-8), AP (***P < 1.0E-9) and propofol (***P = 0.00029; n = 8). The neurosteroid-insensitive α4Q246Mβ3δ was not affected by THDOC (P = 1.0) or AP (P = 0.99), but was potentiated by propofol (**P = 0.0028; n = 7). The little-spontaneous α4β3S409Aδ was potentiated by all modulators, but the effect was not statistically significant for some (THDOC: P = 0.054, AP: *P = 0.011, propofol: P = 0.12; n = 7). The non-spontaneous α4β2δ was not potentiated by any modulator (P ≥ 0.63; n = 5). All comparisons used one-way repeated measures ANOVA with Tukey’s post-hoc test. c Pregnenolone sulfate (PS, 10 µM) reduced spontaneous currents of α4β3δ (**P = 0.0023; n = 8), α4Q246Mβ3δ (***P = 0.00060; n = 7) and α4β3S409Aδ receptors (*P = 0.011; n = 7; two-sided paired t-tests). Representative holding current of α4β3δ during PS application is shown below. d Flurazepam (300 nM) potentiated spontaneous currents of α1β3γ2L receptors (*P = 0.011; two-sided paired t-test; n = 7), but not for the benzodiazepine-insensitive α1H101Rβ3γ2L receptor (P = 1.0; two-sided Wilcoxon signed-rank test; n = 6). Representative current of wild-type α1β3γ2L during flurazepam application is shown below. Data are presented as mean values ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ns no significance. Source data are provided as a Source Data file for Fig. 6.
