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Structural domains of the human GABA_A receptor 3 subunit involved in the actions of pentobarbital

Ruggero Serafini, John Bracamontes and Joe Henry Steinbach

1. This study was conducted to search for the residues of the 3 subunit which affect pentobarbital action on the -aminobutyric acid type A (GABA_A) receptor. Three chimeras were constructed by joining the GABA_A receptor 3 subunit to the 1 subunit. For each chimera, the N-terminal sequence was derived from the 3 subunit and the C-terminal sequence from the 1 subunit, with junctions located between the membrane-spanning regions M2 and M3, in the middle of M2, or in M1, respectively.

2. In receptors obtained by the coexpression of 1 with the chimeric subunits, in contrast with those obtained by the coexpression of 1 and 3, pentobarbital exhibited lower potentiation of GABA-evoked responses, and in the direct gating of Cl^- currents, an increase in the EC₅₀ together with a marked decrease in the relative maximal efficacy compared with that of GABA.

3. Estimates of the channel opening probability through variance analysis and single-channel recordings of one chimeric subunit showed that the reduced relative efficacy for gating largely resulted from an increase in gating by GABA, with little change in efficacy of pentobarbital.

4. A fit of the time course of the response by the predictions of a class of reaction schemes is consistent with the conclusion that the change in the concentration dependence of activation by pentobarbital is due to a change in pentobarbital affinity for the receptor. Therefore, the data suggest that residues of the 3 subunit involved in pentobarbital binding to GABA_A receptors are located downstream from the middle of the M2 region.

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