Abstract
The anxiolytic, hypnotic, and anti-convulsant properties of benzodiazepines (BDZs) require modulation of distinct GABAA receptor α-subtypes. BDZ modulation of GABAA receptors is often described in terms of increased opening frequency, and contrasted with the increased open durations occurring with barbiturate modulation. Several studies spanning single channel, rapid kinetic, and whole cell techniques have suggested that BDZs effect this observed change in frequency through increased affinity for GABA. BDZ-sensitive αβγ isoforms exist at extrasynaptic as well as synaptic locations, where they encounter markedly different concentration and time-course of GABA exposure. Interestingly, this affinity-based mechanism (specifically, decreasing the GABA unbinding rate) is only predicted to increase opening frequency under conditions that allow the unbinding and rebinding cycles typical of prolonged exposure to low GABA concentrations, which are more likely to occur at extrasynaptic GABAA receptors. In contrast, when rebinding is less likely, such as may occur in certain synaptic conditions, the number, but not the frequency, of channel openings increases in response to BDZ modulation. In conclusion, not only can multiple kinetic mechanisms alter channel opening frequency, but a single mechanism – increased affinity – impacts opening frequency differently under different contexts of GABAA receptor activation.
Highlights
The therapeutic importance of benzodiazepines (BDZs) spans multiple clinical domains, including seizures, anxiety, insomnia, and muscle relaxation
After studies of recombinant receptors demonstrated that point mutations in α subtypes effectively compromise BDZ modulation (α1(H101R), α2(H101R), α3(H126R), and α5(H105R)), mice harboring these mutations demonstrated that clinically relevant behavioral effects of BDZs were linked to GABAA receptors containing these α subtypes
The α1-containing receptors were linked to the sedative effects of BZDs [10, 47], and behavioral and EEG characteristics of sleep were insensitive to diazepam in these transgenic mice [52]
Summary
The therapeutic importance of benzodiazepines (BDZs) spans multiple clinical domains, including seizures, anxiety, insomnia, and muscle relaxation. The α1-containing receptors were linked to the sedative effects of BZDs [10, 47], and behavioral and EEG characteristics of sleep were insensitive to diazepam in these transgenic mice [52]. Some overlap in functional roles among the α subtypes is likely, given findings such as the abolished sleep EEG effects of BDZs in the α2 knock-in [25], and the partial compromise of anticonvulsant activity of the α1 knock-in. These knock-in mutations may affect baseline neurophysiology, as
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