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Natural mutation of GABAA receptor α6 subunit alters benzodiazepine affinity but not allosteric GABA effects

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Seeburg,  Peter H.
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Korpi, E. R., & Seeburg, P. H. (1993). Natural mutation of GABAA receptor α6 subunit alters benzodiazepine affinity but not allosteric GABA effects. European Journal of Pharmacology, 247(1), 23-27.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0019-AAD8-B
Abstract
The binding of the imidazobenzodiazepine, [3H]Ro 15-4513, to cerebellar granule cell-specific GABAA/benzodiazepine receptors is typically insensitive to benzodiazepine receptor agonists such as diazepam. A mutation in the α6 subunit, causing replacement of the arginine at the 100 position by glutamine (Q100), has recently been found in an alcohol- and benzodiazepine-sensitive rat line. The mutant α6(Q100)β2γ2 recombinant receptors are sensitive to diazepam. The binding of [3H]Ro 15-4513 to cerebellar diazepam-insensitive receptors is enhanced by GABA, whereas binding to diazepam-sensitive receptors is inhibited. Recombinant receptors consisting of β2 and γ2 subunits together with the wildtype α6 or mutant α6(Q100) subunit showed positive modulation of [3H]Ro 15-4513 binding by GABA, whereas α1β2γ2 receptors showed negative modulation. The picrotoxin-sensitive binding of a convulsant, t-butylbicyclophosphoro[35S]thionate ([35S]TBPS),was inhibited in the α6β2γ2 and α6(Q100)β2γ2 receptors by GABA at concentrations less than one-tenth of those required in the α1β2γ2 receptors. GABA effects on [35S]TBPS binding were only slightly affected by diazepam in the α6(Q100)β2γ2 receptors, while profound effects were seen in the α1β2γ2 receptors in the presence of diazepam. The results with the mutant receptor suggest that the α1 and α6 subunits are responsible for differential allosteric actions by GABA on other binding sites, independently of the structures defining the benzodiazepine binding pharmacology.