Influences on blockade by t ‐butylbicyclo‐phosphoro‐thionate of GABA A receptor spontaneous gating, agonist activation and desensitization

Non‐technical summary  The convulsant t ‐butylbicyclophosphorothionate (TBPS) is considered a GABA A receptor (GABA A R) open channel blocker. However, the relationship between the functional state of the receptor and TBPS binding remains unclear. Radiolabelled [ 35 S]TBPS binds to GABA A Rs in the absence of GABA, suggesting that access to the binding site is independent of activation. Furthermore, low concentrations of GABA enhance [ 35 S]TBPS binding, while higher concentrations reduce binding. Using either bicuculline or the α1(K278M) mutant GABA A R subunit to disrupt function, we demonstrate roles for spontaneous gating, GABA‐evoked channel activation and desensitization in the three phases of [ 35 S]TBPS binding. These findings provide a framework for using [ 35 S]TBPS binding to identify deficits in GABA A R function.