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The Journal of Neuroscience, April 15, 1999, 19(8):2960-2973

Single-Channel Properties of Synaptic and Extrasynaptic GABAA Receptors Suggest Differential Targeting of Receptor Subtypes

Stephen G. Brickley, Stuart G. Cull-Candy, and Mark Farrant

Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Many neurons express a multiplicity of GABAA receptor subunit isoforms. Despite having only a single source of inhibitory input, the cerebellar granule cell displays, at various stages of development, more than 10 different GABAA subunit types. This subunit diversity would be expected to result in significant receptor heterogeneity, yet the functional consequences of such heterogeneity remain poorly understood. Here we have used single-channel properties to characterize GABAA receptor types in the synaptic and extrasynaptic membrane of granule cells. In the presence of high concentrations of GABA, which induced receptor desensitization, extrasynaptic receptors in outside-out patches from the soma entered long-lived closed states interrupted by infrequent clusters of openings. Each cluster of openings, which is assumed to result from the repeated activation of a single channel, was to one of three main conductance states (28, 17, or 12 pS), the relative frequency of which differed between patches. Such behavior indicates the presence of at least three different receptor types. This heterogeneity was not replicated by individual recombinant receptors (alpha 1beta 2gamma 2S or alpha 1beta 3gamma 2S), which gave rise to clusters of a single type only. By contrast, the conductance of synaptic receptors, determined by fluctuation analysis of the synaptic current or direct resolution of channel events, was remarkably uniform and similar to the highest conductance value seen in extrasynaptic patches. These results suggest that granule cells express multiple GABAA receptor types, but only those with a high conductance, most likely containing a gamma  subunit, are activated at the synapse.

Key words: cerebellar granule cell; GABAA receptor; synaptic; single channel; subunit heterogeneity; differential targeting

Copyright © 1999 Society for Neuroscience  0270-6474/99/1982960-14$05.00/0


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