Activation of the Rat α1β2ε GABAA Receptor by Orthosteric and Allosteric Agonists

Allison L. Germann, Ariel B. Burbridge, Spencer R. Pierce, Gustav Akk

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


GABAA receptors are a major contributor to fast inhibitory neurotransmission in the brain. The receptors are activated upon binding the transmitter GABA or allosteric agonists including a number of GABAergic anesthetics and neurosteroids. Functional receptors can be formed by various combinations of the nineteen GABAA subunits cloned to date. GABAA receptors containing the ε subunit exhibit a significant degree of constitutive activity and have been suggested to be unre-sponsive to allosteric agents. In this study, we have characterized the functional properties of the rat α1β2ε GABAA receptor. We confirm that the α1β2ε receptor exhibits a higher level of constitutive activity than typical GABAA receptors and show that it is inefficaciously activated by the transmitter and the allosteric agonists, propofol, pentobarbital, and allopregnanolone. Manipulations intended to alter ε subunit expression and receptor stoichiometry were largely without effect on receptor properties including sensitivity to GABA and allosteric agonists. Surprisingly, amino acid substitu-tions at the conserved 9’ and 6’ positions in the second transmembrane (TM2) domain in the ε sub-unit did not elicit the expected functional effects of increased constitutive activity and resistance to the channel blocker picrotoxin, respectively. We tested the accessibility of TM2 residues mutated to cysteine using the cysteine‐modifying reagent 4‐(hydroxymercuri)benzoic acid and found a unique pattern of water‐accessible residues in the ε subunit.

Original languageEnglish
Article number868
Issue number7
StatePublished - Jul 2022


  • GABAA receptor
  • activation
  • allosteric agonist
  • orthosteric agonist
  • potentiation


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