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GABA beyond the synapse: defining the subtype‐specific pharmacodynamics of non‐synaptic GABAA receptors

Physiologically relevant combinations of recombinant GABAA receptor (GABAR) subunits were expressed in HEK293 cells. Using whole‐cell voltage clamp and rapid drug application, we measured the GABAR‐subtype‐specific properties to convey either synaptic or extrasynaptic signalling in a range of physiological contexts. α4βδ GABARs are optimally tuned to submicromolar tonic GABA and transient surges of micromolar GABA concentrations. α5β2γ2l GABARs are better suited to higher tonic GABA levels, but also convey robust responses to brief synaptic and perisynaptic GABA fluctuations. α1β2/3δ GABARs function well at prolonged, micromolar (>2 μm) GABA levels, but not to low tonic (<1 μm GABA) or synaptic/transient GABAergic signalling. These results help illuminate the context‐ and isoform‐specific modes of GABAergic signalling in the brain.