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MOLECULAR AND GENOMIC |
4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA
Departments of
1 Neurology
2 Molecular Physiology & Biophysics
3 Pharmacology
4 Program in Neuroscience,Vanderbilt University, Nashville, TN 37212, USA
Up-regulation of the GABAA receptor 
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 4 subtype-containing GABAA receptors in normal and abnormal physiology. We used rapid GABA application to recombinant GABAA receptors expressed in HEK293T cells to compare the macroscopic kinetic properties of 4
3
2L receptors to those of the more widely distributed 132L receptors. These receptor currents had similar peak current amplitudes and GABA EC50 values. However, 432L currents activated more slowly when exposed to submaximal GABA concentrations, had more fast desensitization (
= 15–100 ms), and had less residual current during long GABA applications. In addition, 432L currents deactivated more slowly than 132L currents. Peak currents evoked by repetitive, brief GABA applications were more strongly attenuated for 432L currents than 132L currents. Moreover, the time required to recover from desensitization was prolonged in 432L currents compared to 132L 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 432L currents to higher concentrations of GABA, while 132L currents were less affected by exposure to low levels of GABA. Taken together, these data suggest that 432L receptors have unique kinetic properties that limit the range of GABA applications to which they can respond maximally. While similar to 132L receptors in their ability to respond to brief and low frequency synaptic inputs, 432L receptors are less efficacious when exposed to prolonged tonic GABA or during repetitive stimulation, as may occur during learning and seizures.
(Received 6 October 2006;
accepted after revision 22 November 2006;
first published online 23 November 2006)
Corresponding author A. Lagrange: Vanderbilt University Medical Centre, 6140 Medical Research Building III, 465 21st Ave, South, Nashville, TN 37232-8552, USA. Email: andre.h.lagrange{at}vanderbilt.edu
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