Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits

FEBS Lett. 1998 Jul 24;431(3):400-4. doi: 10.1016/s0014-5793(98)00803-5.


Amino acids in the alpha- and gamma-subunits contribute to the benzodiazepine binding site of GABA(A)-receptors. We show that the mutation of a conserved histidine residue in the N-terminal extracellular segment (alpha1H101R, alpha2H101R, alpha3H126R, and alpha5H105R) results not only in diazepam-insensitivity of the respective alphaxbeta2,3gamma2-receptors but also in an increased potentiation of the GABA-induced currents by the partial agonist bretazenil. Furthermore, Ro 15-4513, an inverse agonist at wild-type receptors, acts as an agonist at all mutant receptors. This conserved molecular switch can be exploited to identify the pharmacological significance of specific GABA(A)-receptor subtypes in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Azides / pharmacology
  • Base Sequence
  • Benzodiazepines / pharmacology
  • Benzodiazepinones / pharmacology
  • Cell Line
  • Diazepam / pharmacology*
  • Humans
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligodeoxyribonucleotides
  • Patch-Clamp Techniques
  • Rats
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / genetics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / genetics


  • Azides
  • Benzodiazepinones
  • Oligodeoxyribonucleotides
  • Receptors, GABA-A
  • Recombinant Proteins
  • Benzodiazepines
  • Ro 15-4513
  • bretazenil
  • Diazepam