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1 Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK2 Department of Pharmacology, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen Ø, Denmark3 Department of Molecular Pharmacology, H. Lundbeck A/S, Otilliavej 8, 2500 Valby, Copenhagen, Denmark4 Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
The linkage between agonist binding and the activation of a GABAA receptor ion channel is yet to be resolved. This aspect was examined on human recombinant 
1ß2
2S GABAA receptors expressed in human embryonic kidney cells using the following series of receptor agonists: GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), isonipecotic acid, piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid (IAA), 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL) and 5-(4-piperidyl)-3-isoxazolol (4-PIOL). Whole-cell concentration–response curves enabled the agonists to be categorized into four classes based upon their maximum responses. Single channel analyses revealed that the channel conductance of 25–27 pS was unaffected by the agonists. However, two open states were resolved from the open period distributions with mean open times reduced 5-fold by the weakest partial agonists. Using saturating agonist concentrations, estimates of the channel shutting rate, , ranged from 200 to 600 s–1. The shut period distributions were described by three or four components and for the weakest partial agonists, the interburst shut periods increased whilst the mean burst durations and longest burst lengths were reduced relative to the full agonists. From the burst analyses, the opening rates for channel activation, ß, and the total dissociation rates, k–1, for the agonists leaving the receptor were estimated. The agonist efficacies were larger for the full agonists (E
7–9) compared to the weak partial agonists (0.4–0.6). Overall, changes in agonist efficacy largely determined the different agonist profiles with contributions from the agonist affinities and the degree of receptor desensitization. From this we conclude that GABAA receptor activation does not occur in a switch-like manner since the agonist recognition sites are flexible, accommodating diverse agonist structures which differentially influence the opening and shutting rates of the ion channel.
(Received 8 September 2003;
accepted after revision 25 February 2004;
first published online 27 February 2004)
Corresponding author T. G. Smart: Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: t.smart{at}ucl.ac.uk
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