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

GABA(A) receptors (GABARs) mediate a remarkable diversity of signalling modalities in vivo. Yet most published work characterizing responses to GABA has focused on the properties needed to convey fast, phasic synaptic inhibition. We therefore aimed to characterize the most prevalent (alpha 4 beta delta, alpha 5 beta 3 gamma 2L) and least prevalent (12) non-synaptic 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 alpha 4 beta delta GABARs were very sensitive to submicromolar GABA, with a rank order potency of alpha 4 beta 2 delta >= alpha 4 beta 1 delta approximate to alpha 4 beta 3 delta GABARs. In comparison, the GABA EC50 was up to 20 times higher for alpha 4 beta 2 delta L GABARs, with alpha 1 beta 2 delta and alpha 5 beta 3 gamma 2L GABARs having intermediate GABA potency. Both alpha 4 beta delta and alpha 5 beta 3 gamma 2L 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 alpha 4 beta 2 delta (0.1-1 mu m), alpha 5 beta 3 gamma 2L (0.5-7 mu m) and alpha 1 beta 2 gamma 2L (0.6-9 mu m) GABARs. Finally, alpha 1 beta 2 delta 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 non-synaptic 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.