Enhanced macroscopic desensitization shapes the response of α4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA

Up-regulation of the GABA(A) receptor alpha 4 subunit subtype has been consistently shown in multiple animal models of chronic epilepsy. This isoform is expressed in both thalamus and hippocampus and is likely to play a significant role in regulating corticothalamic and hippocampal rhythms. However, little is known about its physiological properties, thus limiting understanding of the role of alpha 4 subtype-containing GABA(A) receptors in normal and abnormal physiology. We used rapid GABA application to recombinant GABA(A) receptors expressed in HEK293T cells to compare the macroscopic kinetic properties of alpha 4 beta 3 gamma 2L receptors to those of the more widely distributed alpha 1 beta 3 gamma 2L receptors. These receptor currents had similar peak current amplitudes and GABA EC50 values. However, alpha 4 beta 3 gamma 2L currents activated more slowly when exposed to submaximal GABA concentrations, had more fast desensitization (tau = 15-100 ms), and had less residual current during long GABA applications. In addition, alpha 4 beta 3 gamma 2L currents deactivated more slowly than alpha 1 beta 3 gamma 2L currents. Peak currents evoked by repetitive, brief GABA applications were more strongly attenuated for alpha 4 beta 3 gamma 2L currents than alpha 1 beta 3 gamma 2L currents. Moreover, the time required to recover from desensitization was prolonged in alpha 4 beta 3 gamma 2L currents compared to alpha 1 beta 3 gamma 2L currents. We also found that exposure to prolonged low levels of GABA, similar to those that might be present in the extrasynaptic space, greatly suppressed the response of alpha 4 beta 3 gamma 2L currents to higher concentrations of GABA, while alpha 1 beta 3 gamma 2L currents were less affected by exposure to low levels of GABA. Taken together, these data suggest that alpha 4 beta 3 gamma 2L receptors have unique kinetic properties that limit the range of GABA applications to which they can respond maximally. While similar to alpha 1 beta 3 gamma 2L receptors in their ability to respond to brief and low frequency synaptic inputs, alpha 4 beta 3 gamma 2L receptors are less efficacious when exposed to prolonged tonic GABA or during repetitive stimulation, as may occur during learning and seizures.