Allosteric modulation of GABAA receptors via multiple drug-binding sites

Adv Pharmacol. 2015;72:53-96. doi: 10.1016/bs.apha.2014.10.002. Epub 2014 Dec 4.


GABAA receptors are ligand-gated ion channels composed of five subunits that can be opened by GABA and be modulated by multiple pharmacologically and clinically important drugs. Over the time, hundreds of compounds from different structural classes have been demonstrated to modulate, directly activate, or inhibit GABAA receptors, and most of these compounds interact with more than one binding site at these receptors. Crystal structures of proteins and receptors homologous to GABAA receptors as well as homology modeling studies have provided insights into the possible location of ligand interaction sites. Some of these sites have been identified by mutagenesis, photolabeling, and docking studies. For most of these ligands, however, binding sites are not known. Due to the high flexibility of GABAA receptors and the existence of multiple drug-binding sites, the unequivocal identification of interaction sites for individual drugs is extremely difficult. The existence of multiple GABAA receptor subtypes with distinct subunit composition, the contribution of distinct subunit sequences to binding sites of different receptor subtypes, as well as the observation that even subunits not directly contributing to a binding site are able to influence affinity and efficacy of drugs, contribute to a unique pharmacology of each GABAA receptor subtype. Thus, each receptor subtype has to be investigated to identify a possible subtype selectivity of a compound. Although multiple binding sites make GABAA receptor pharmacology even more complicated, the exploitation of ligand interaction with novel-binding sites also offers additional possibilities for a subtype-selective modulation of GABAA receptors.

Keywords: Allosteric modulation; GABA(A) receptor structure; Ligand-binding sites; Pharmacology; Receptor subtype-selective interactions.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Binding Sites
  • GABA Modulators / pharmacology*
  • Humans
  • Ligands
  • Models, Biological*
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / metabolism


  • GABA Modulators
  • Ligands
  • Receptors, GABA-A