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First published online on October 5, 2006.
 Copyright © 2006 by The Physiological Society
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Received July 26, 2006
Revised August 31, 2006
Accepted after revision October 4, 2006

Extrasynaptic {alpha}{beta} subunit GABAA receptors on rat hippocampal pyramidal neurons

Martin Mortensen1 and Trevor G Smart1*

1 UCL

* To whom correspondence should be addressed. E-mail: t.smart{at}ucl.ac.uk.

Extrasynaptic GABAA receptors that are tonically-activated by ambient GABA are important for controlling neuronal excitability. In hippocampal pyramidal neurons, the subunit composition of these extrasynaptic receptors may include {alpha}5{beta}{gamma} and/or {alpha}4{beta}{delta} subunits. Our present studies reveal that a component of the tonic current in the hippocampus is highly-sensitive to inhibition by Zn2+. This component is probably not mediated by either {alpha}5{beta}{gamma} or {alpha}4{beta}{delta} receptors, but might be explained by the presence of {alpha}{beta} isoforms. Using patch clamp recording from pyramidal neurons, a small tonic current measured in the absence of exogenous GABA exhibited both high and low sensitivity to Zn2+ inhibition (IC50s: 1.89 and 223 µM). Using low nanomolar and micromolar GABA concentrations to replicate tonic currents, we identified two components that are mediated by benzodiazepine-sensitive and -insensitive receptors. The latter indicated that extrasynaptic GABAA receptors exist which are devoid of {gamma}2 subunits. To distinguish whether the benzodiazepine-insensitive receptors were {alpha}{beta} or {alpha}{beta}{delta} isoforms, we used single channel recording. Expressing recombinant {alpha}1{beta}3{gamma}2, {alpha}5{beta}3{gamma}2,fn{alpha}4{beta}3{delta} and {alpha}1{beta}3 receptors in HEK or Ltk cells, revealed similar openings with high main conductances (~25-28 pS) for {gamma}2 or {delta} subunit-containing receptors whilst {alpha}{beta} receptors were characterised by a lower main conductance state (~11 pS). Recording from pyramidal cell somata revealed a similar range of channel conductances, indicative of a mixture of GABAA receptors in the extrasynaptic membrane. The lowest conductance state (~11 pS) was the most sensitive to Zn2+ inhibition in accord with the presence of {alpha}{beta} receptors. This receptor type is estimated to account for up to 10 % of all extrasynaptic GABAA receptors on hippocampal pyramidal neurons.


Key words: GABA receptor • Inhibition • Single channel




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