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Journal Article

Benzodiazepine-induced motor impairment linked to point mutation in cerebeilar GABAA receptor

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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., Kleingoor, C., Kettenmann, H., & Seeburg, P. H. (1993). Benzodiazepine-induced motor impairment linked to point mutation in cerebeilar GABAA receptor. Nature, 361, 356-359. doi:10.1038/361356a0.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0019-AADA-7
Abstract
THE selectively outbred alcohol-non-tolerant (ANT) rat line1 is highly susceptible to impairment of postural reflexes by benzodiazepine agonists2 such as diazepam. ANT cerebella are generally devoid3 of diazepam-insensitive high-affinity binding of the benzodiazepine [3H]Ro 15-4513 (refs 4, 5), whereas in non-selected strains such binding marks a granule-cell-specific GABAA (γ-aminobutyric acid) receptor containing the α6 subunit5,6. A critical determinant for diazepam insensitivity of this ‘wild-type’ cerebeilar GABAA receptor is an arginine residue7 in α6 position 100, where other a subunits carry a histidine8. Here we report that the ct6 gene of ANT rats is expressed at wild-type levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. In consequence, α6(Q 100)β2γ2 receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of [3H]Rol5-4513. Our results suggest that cerebeilar motor control may be a distinct behavioural correlate of the a6-subunit-containing GABAA receptor subtype.