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Influences on blockade by t ‐butylbicyclo‐phosphoro‐thionate of GABA A receptor spontaneous gating, agonist activation and desensitization
Author(s) -
Othman Nidaa A.,
Gallacher Michael,
Deeb Tarek Z.,
BaptistaHon Daniel T.,
Perry David C.,
Hales Tim G.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2011.213249
Subject(s) - picrotoxin , bicuculline , chemistry , gabaa receptor , agonist , gating , blockade , receptor , gaba receptor antagonist , desensitization (medicine) , pharmacology , neuroscience , biophysics , biochemistry , biology
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.