Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor.
The selectively outbred alcohol-non-tolerant (ANT) rat line is highly susceptible to impairment of postural reflexes by benzodiazepine agonists such as diazepam. ANT cerebella are generally devoid of diazepam-insensitive high-affinity binding of the benzodiazepine [3H]Ro15-4513, whereas in non-selected strains such binding marks a granule-cell-specific GABAA (gamma-aminobutyric acid) receptor containing the alpha 6 subunit. A critical determinant for diazepam insensitivity of this 'wild-type' cerebellar GABAA receptor is an arginine residue in alpha 6 position 100, where other alpha subunits carry a histidine. Here we report that the alpha 6 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, alpha 6(Q100)beta 2 gamma 2 receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of [3H]Ro15-4513. Our results suggest that cerebellar motor control may be a distinct behavioural correlate of the alpha 6-subunit-containing GABAA receptor subtype.
Korpi
E R
ER
Laboratory of Molecular Neuroendocrinology, University of Heidelberg, Germany.
Kleingoor
C
C
Kettenmann
H
H
Seeburg
P H
PH
D000345:Affinity Labels / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine; D001345:Autoradiography; D001386:Azides / Q000378:metabolism; D001483:Base Sequence; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive; D002531:Cerebellum / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D004361:Drug Tolerance / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D006639:Histidine; D017403:In Situ Hybridization; D007700:Kinetics; D046911:Macromolecular Substances; D008961:Models, Structural; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects*; D009838:Oligodeoxyribonucleotides; D017354:Point Mutation; D011061:Poly A / Q000235:genetics / Q000302:isolation & purification; D017433:Protein Structure, Secondary; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000345:Affinity Labels; D001386:Azides; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D011061:Poly A; D000431:Ethanol; D006639:Histidine; D005680:gamma-Aminobutyric Acid; D012313:RNA; C042957:Ro 15-4513; D001120:Arginine; D003975:Diazepam