Distinct activities of GABA agonists at synaptic‐ and extrasynaptic‐type GABA A receptors

The activation characteristics of synaptic and extrasynaptic GABA A receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7‐tetrahydoisoxazolo[5,4‐c]pyridin‐3(2 H )‐one (THIP), to further understand the activation profiles of α1β3γ2, α4β3γ2 and α4β3δ receptors that typify synaptic‐ and extrasynaptic‐type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At δ subunit‐containing extrasynaptic‐type GABA A receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole‐cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on α4β3δ receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic‐type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. Nerve cell excitability is controlled by the brain neurotransmitter gamma‐aminobutyric acid (GABA), which activates Cl − channels called GABA A receptors. They are located at two major sites, synapses and neighbouring extrasynaptic regions, where they display different subunit compositions. The properties of these receptors were explored using GABA and two other activating drugs. Of these, the sleep inducing drug THIP caused the greatest activation of extrasynaptic receptors by a process known as superagonism. The molecular mechanism underlying this phenomenon was linked to longer and more frequent activation of the extrasynaptic Cl − channels. Clinically, THIP can induce sleep and reduce anxiety, which suggests that extrasynaptic GABA A receptors are significantly involved, and are likely to be important future drug targets.