Extended Data Fig. 5: GABA and histamine crosstalk happens at the level of individual α4β3δ receptors.
From: Differential assembly diversifies GABAA receptor structures and signalling
To address the complexity arising from the presence of multiple receptor subtypes, we investigated the modulation of 100 nM GABA currents by 300 μM histamine in cells expressing different combinations of α4, β3 and δ subunits. We first established that 100 nM GABA robustly activates currents in α4β3δ cells (n = 6 cells) (a), barely in α4β3 (n = 5 cells) (b) and not in β3δ (n = 6 cells) (c) or β3 cells (n = 4 cells) (d). Histamine at 300 μM robustly enhances the GABA current in α4β3δ cells but only modestly in the α4β3, β3δ and β3 cells. The modest enhancement is attributable to histamine currents alone (e.g., from the β3δ or β3-homomeric subtypes). Representative current traces from three successive pulses separated by 1 min: (1) 8 s pulse of 100 nM GABA (dark green); (2) 8 s pulse of 100 nM GABA with a 4 s notch of 300 μM histamine added after two seconds (blue), and (3) 8 s pulse of 100 nM GABA (light green). Finally, to open all receptor isoforms, a normalization pulse of (10 mM GABA + 30 μM etomidate) was applied. e, Histamine enhances GABA current strongly only in α4β3δ receptors (P < 0.0001, one-way ANOVA). Scatter plot shows peak current amplitudes of the blue traces in panels a–d, normalized to the total cell current (10 mM GABA + 30 μM etomidate). Data are presented as mean ± SD. Sample size is the same as in panels a–d.
