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Does the organisation of native GABAA receptors affect their ion channel properties?

V.A.L. Seymour, T. Luu, P.W. Gage and M.L. Tierney, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.

The GABAA receptor is responsible for fast inhibitory neural transmission in the mammalian brain. Native Receptors are clustered at inhibitory synapses and are also found both clustered and non-clustered at other sites on the neuronal cell surface (extrasynaptic). The GABAA receptor is the target of many drugs including benzodiazepines such as diazepam and general anaesthetics such as etomidate. The functional behaviour of native GABAA receptors is complex. Much of the receptor’s functional complexity has been attributed to its extensive structural heterogeneity (19 genes). The single channel properties of native GABAA receptors are different to recombinant GABAA receptors. The conductance of recombinant receptors never exceeds 40 pS and is not modulated by drugs unlike native receptors which have conductance’s exceeding 80 pS and conductance may be modulated by drugs. However, when the trafficking protein GABARAP is coexpressed with recombinant α1β1γ2s subsubunit receptors the channel properties mimic neuronal extrasynaptic GABAA receptors and their dispersion in the membrane changes such that they form clusters. We have used the patch clamp technique to compare the single channel properties of neuronal extrasynaptic GABAA receptors with recombinant α1β1γ2s receptors ± GABARAP. We have found a linear correlation between higher conductances and longer mean open times in GABAA receptors from both native and recombinant systems. The results suggest that both receptor diversity and receptor organisation may play a role in the plasticity of the GABAA response.