Prince, Richard John; (1992) Allosteric interactions of gaba- and glycine-gated chloride channels from rat brain. Doctoral thesis (Ph.D.), University College London.

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Abstract

The allosteric interactions of the GABAA receptor were investigated through the actions of drugs on [3H]-flunitrazepam binding. The effects of varying incubation temperature revealed that pentobarbitone is more efficacious a potentiator at low temperatures than at high. In contrast, the general anaesthetics propofol and alphaxalone did not show a variation in efficacy with temperature. These results argue against a membrane site of action for propofol and alphaxalone. Differences in the dependence of potentiation upon anions were also noted. All three drugs gave increased potentiation with increasing concentrations of anions which can permeate the GABAA receptor. However, whilst the potency of propofol increased with chloride concentration, its efficacy did not. Pentobarbitone showed an increase in both potency and efficacy but whilst alphaxalone's efficacy increased, its potency did not. These results indicate different sites and modes of interaction for propofol, alphaxalone and pentobarbitone. Interactions of the steroid epipregnanolone with the receptor were also characterised. It antagonised competitively the potentiation produced by its isomers pregnanolone and allopregnanolone whilst having little direct effect upon flunitrazepam binding or on potentiation by pentobarbitone and GABA. Epipregnanolone also antagonized the potentiating effect of alphaxalone but the mode of inhibition was different to that seen against pregnanolone, indicating more than one class of binding site for neurosteroids at the GABAA receptor. [3H]-flunitrazepam binding to GABAA receptors immunopurified according to a subunit content was also examined. No potentiation by alphaxalone or pentobarbitone was seen but differences in flunitrazepam affinity and EC50 for potentiation by GABA were noted. In an electrophysiological study, the interaction of steroids with the strychnine-sensitive glycine receptor was examined. Certain corticosteroids were shown to be potent enhancers of the actions of glycine and strychnine at this receptor, but steroids which are active on the GABAA receptor showed no effects.

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