title: Consequence of the presence of two different beta subunit isoforms in a GABA(A) receptor.
abstract: The major isoforms of GABA(A) receptors are thought to be composed of two alpha, two beta and one gamma subunit(s). GABA(A) receptors containing two beta1 subunits respond differently to the anticonvulsive compound loreclezole and the general anaesthetic etomidate than receptors containing two beta2 subunits. Receptors containing beta2 subunits show a much larger allosteric stimulation by these agents than those containing beta1 subunits. We were interested to know how receptors containing both beta1 and beta2 subunits, 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 (alpha1-beta1-alpha1/gamma2-beta1, alpha1-beta2-alpha1/gamma2-beta1, alpha1-beta1-alpha1/gamma2-beta2 and alpha1-beta2-alpha1/gamma2-beta2) 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 beta1 and beta2 subunits in the same pentamer (mixed receptors) direct gating by etomidate is similar to exclusively beta1 containing receptors; (II) In mixed receptors, stimulation by etomidate assumed characteristics intermediate to exclusively beta1 or beta2 containing receptors, but the values for the concentrations < 10 microM were always much closer to those observed in alpha1-beta1-alpha1/gamma2-beta1 receptors; and (III) mixed receptors show no positional effects.
authors.affiliation: Department of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boulineau
authors.forename: Roland
authors.initials: R
authors.lastname: Baur
authors.forename: Frédéric
authors.initials: F
authors.lastname: Minier
authors.forename: Erwin
authors.initials: E
authors.lastname: Sigel
mesh_terms: D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005045:Etomidate / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007536:Isomerism; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018755:GABA Agonists; C502185:Gabrb2 protein, rat; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D014230:Triazoles; D005680:gamma-Aminobutyric Acid; C066440:loreclezole; D004247:DNA; D005045:Etomidate