GABA beyond the synapse-defining the subtype-specific pharmacodynamics of nonsynaptic GABAA receptors.
J Physiol. 2018 Jul 17;:
Authors: Lagrange AH, Hu N, Macdonald RL
GABAA receptors (GABARs) mediate a remarkable diversity of signalling modalities in vivo. Yet most published work characterizing responses to GABA have focused on the properties needed to convey fast, phasic synaptic inhibition. We therefore aimed to characterize the most prevalent (α4βδ, α5β3γ2L) and least prevalent (α1β2δ) nonsynaptic GABAR currents, using whole-cell voltage clamp recordings of recombinant GABAR expressed in HEK293 cells and drug application protocols to recapitulate the GABA concentration profiles occurring during both fast synaptic and slow extrasynaptic signalling. We found that α4βδ GABARs were very sensitive to submicromolar GABA, with a rank order potency of α4β2δ ≥ α4β1δ ≈ α4β3δ GABARs. In comparison, the GABA EC50 was up to twenty times higher for α1β2γ2L GABARs, with α1β2δ and α5β3γ2L GABARs having intermediate GABA potency. Both α4βδ and α5β3γ2L GABAR currents exhibited slow, but substantial, desensitization as well as prolonged rates of deactivation. These GABAR current properties defined distinct “dynamic ranges” of responsiveness to changing GABA for α4β2δ (0.1-1 μm), α5β3γ2L (0.5-7 μm) and α1β2γ2L (0.6-9 μm) GABARs. Finally, α1β2δ GABARs were notable for their relative lack of desensitization and extremely quick deactivation. In summary, our results help delineate the roles that specific GABARs may play in mediating nonsynaptic GABA signals. Since ambient GABA levels may be altered during development as well as by drugs and disease states, these findings may help future efforts to understand disrupted inhibition underlying a variety of neurological illnesses, such as epilepsy. This article is protected by copyright. All rights reserved.
PMID: 30019335 [PubMed – as supplied by publisher]