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The Journal of Neuroscience, November 1, 1998, 18(21):8590-8604
Defining Affinity with the GABAA Receptor
Mathew V. Jones1, Yoshinori Sahara1, 2, Jeffrey A. Dzubay1, and Gary L. Westbrook1, 3 1 Vollum Institute and 3 Department of Neurology, Oregon Health Sciences University, Portland, Oregon 97201, and 2 Department of Physiology, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo 113, Japan
At nicotinic and glutamatergic synapses, the duration of the postsynaptic response depends on the affinity of the receptor for transmitter (; ). Affinity is often thought to be determined by the ligand unbinding rate, whereas the binding rate is assumed to be diffusion-limited. In this view, the receptor selects for those ligands that form a stable complex on binding, but binding is uniformly fast and does not itself affect selectivity. We tested these assumptions for the GABAA receptor by dissecting the contributions of microscopic binding and unbinding kinetics for agonists of equal efficacy but of widely differing affinities. Agonist pulses applied to outside-out patches of cultured rat hippocampal neurons revealed that agonist unbinding rates could not account for affinity if diffusion-limited binding was assumed. However, direct measurement of the instantaneous competition between agonists and a competitive antagonist revealed that binding rates were orders of magnitude slower than expected for free diffusion, being more steeply correlated with affinity than were the unbinding rates. The deviation from diffusion-limited binding indicates that a ligand-specific energy barrier between the unbound and bound states determines GABAA receptor selectivity. This barrier and our kinetic observations can be quantitatively modeled by requiring the participation of movable elements within a flexible GABA binding site.
Key words: ligand-gated channels; kinetics; selectivity; molecular modeling; synapse; thermodynamic
Copyright © 1998 Society for Neuroscience 0270-6474/98/18218590-15$05.00/0
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