Consequence of the presence of two different β subunit isoforms in a GABAAreceptor

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Abstract
The major isoforms of GABAAreceptors are thought to be composed of two α, two β and one γ subunit(s). GABAAreceptors containing two β1subunits respond differently to the anticonvulsive compound loreclezole and the general anaesthetic etomidate than receptors containing two β2subunits. Receptors containing β2subunits show a much larger allosteric stimulation by these agents than those containing β1subunits. We were interested to know how receptors containing both β1and β2subunits, in different positions respond to loreclezole and etomidate. To answer this question, subunits were fused at the DNA level to form dimeric and trimeric subunits. Concatenated receptors (α1‐β1‐α1/γ2‐β1, α1‐β2‐α1/γ2‐β1, α1‐β1‐α1/γ2‐β2and α1‐β2‐α1/γ2‐β2) were expressed in Xenopus ooctyes and functionally compared in their response to the agonist GABA and to the positive allosteric modulators, loreclezole and etomidate. We have shown that (I) in the presence of both β1and β2subunits in the same pentamer (mixed receptors) direct gating by etomidate is similar to exclusively β1containing receptors; (II) In mixed receptors, stimulation by etomidate assumed characteristics intermediate to exclusively β1or β2containing receptors, but the values for the concentrations < 10 µmwere always much closer to those observed in α1‐β1‐α1/γ2‐β1receptors; and (III) mixed receptors show no positional effects.