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

Nature. 1993 Jan 28;361(6410):356-9. doi: 10.1038/361356a0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affinity Labels / metabolism
  • Amino Acid Sequence
  • Animals
  • Arginine*
  • Autoradiography
  • Azides / metabolism
  • Base Sequence
  • Benzodiazepines / metabolism
  • Binding, Competitive
  • Cerebellum / physiology*
  • Diazepam / pharmacology*
  • Drug Tolerance / genetics
  • Ethanol / pharmacology*
  • Histidine*
  • In Situ Hybridization
  • Kinetics
  • Macromolecular Substances
  • Models, Structural
  • Molecular Sequence Data
  • Motor Activity / drug effects*
  • Oligodeoxyribonucleotides
  • Point Mutation*
  • Poly A / genetics
  • Poly A / isolation & purification
  • Protein Structure, Secondary
  • RNA / genetics
  • RNA / isolation & purification
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Mutant Strains
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / genetics*
  • Receptors, GABA-A / physiology
  • Tritium
  • gamma-Aminobutyric Acid / pharmacology*

Substances

  • Affinity Labels
  • Azides
  • Macromolecular Substances
  • Oligodeoxyribonucleotides
  • RNA, Messenger
  • Receptors, GABA-A
  • Tritium
  • Benzodiazepines
  • Poly A
  • Ethanol
  • Histidine
  • gamma-Aminobutyric Acid
  • RNA
  • Ro 15-4513
  • Arginine
  • Diazepam