Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism

Nat Neurosci. 2002 Nov;5(11):1163-8. doi: 10.1038/nn926.


Neurotransmitter-operated ion channels, such as the GABA (gamma-aminobutyric acid) receptor, are important in fast synaptic transmission between neurons. Using site-specific fluorescent labeling and simultaneous electrophysiological analysis in Xenopus laevis oocytes expressing recombinant rho1 GABA receptors, we identified agonist-mediated molecular rearrangements at three positions within and near the agonist-binding pocket that were highly correlated with receptor activation. We also show that competitive antagonists induced distinct rearrangements on their own that stabilized the receptor in a closed state. Finally, the allosteric antagonist picrotoxin induced a global conformational change that was sensed in the subunit-subunit interface of the amino (N)-terminal domain, distant from its presumed site of action within the transmembrane domains. This first detection in real time of molecular rearrangements of a ligand-activated receptor provides insights into the structural correlates of activation, antagonism and allosteric modulation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Binding, Competitive / physiology
  • Female
  • Fluorescent Dyes
  • GABA Antagonists / pharmacology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology*
  • Oocytes / physiology
  • Picrotoxin / pharmacology
  • Protein Structure, Tertiary
  • Receptors, GABA / chemistry*
  • Receptors, GABA / physiology*
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship
  • Xenopus laevis
  • gamma-Aminobutyric Acid / pharmacology


  • Fluorescent Dyes
  • GABA Antagonists
  • Receptors, GABA
  • Recombinant Proteins
  • Picrotoxin
  • gamma-Aminobutyric Acid