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Single-channel properties of neuronal GABA_A receptors from mice lacking the 2 subunit

Matthias Lorez, Dietmar Benke, Bernhard Lüscher, Hanns Möhler and Jack A. Benson

1. The aim of this study was to define the biophysical properties contributed by the 2 subunit to native single GABA_A receptors.

2. Single-channel activity was recorded from neurones of wild-type (2+/+) mice and compared with that from mice which were heterozygous (2+/-) or homozygous (2-/-) for a targeted disruption in the 2 subunit gene of the GABA_A receptor. Unitary currents were evoked by low concentrations of GABA (0·5-5 µM) in membrane patches from acutely isolated dorsal root ganglion (DRG) neurones (postnatal day 0) and by 1 µM GABA in patches from embryonic hippocampal neurones which were cultured for up to 3 weeks.

3. GABA_A receptors from DRG and hippocampal neurones of 2+/+ and 2+/- mice displayed predominantly a conductance state of 28 pS and less frequently 18 and 12 pS states. In 2-/- mice, conductance states mainly of 12 pS and less frequently of 24 pS were found.

4. The mean open duration of the 28 pS state in 2+/+ GABA_A receptors (1·5-2·6 ms) was substantially longer than for the 12 pS state of 2-/- GABA_A receptors (0·9-1·2 ms) at all GABA concentrations. For 2+/+ and 2-/- channels, the mean open duration was increased at higher GABA concentrations.

5. Open duration frequency distributions of 28 and 12 pS receptors revealed the existence of at least three exponential components. Components with short mean durations declined and components with long mean durations increased in relative frequency at higher GABA concentration indicating at least two binding sites of GABA per 28 and 12 pS receptor.

6. Shut time frequency distributions revealed at least four exponential components of which two were identified as intraburst components in 28 pS and one in 12 pS GABA_A receptors.

7. The mean burst duration and the mean number of openings per burst increased in 28 and 12 pS GABA_A receptors with increasing GABA concentration. At least two burst types were identified: simple bursts consisting of single openings and complex bursts of five to six openings in 28 pS but only two to three openings in 12 pS GABA_A receptors.

8. We conclude that the 2 subunit enhances the efficacy of GABA by determining open conformations of high conductance and long lifetime, and by prolonging the time receptors remain in the activated bursting state.

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