%0 Journal Article %A Kate K O'Toole %A Andrew Jenkins %T The Apparent Voltage Dependence of GABAA Receptor Activation and Modulation is Inversely Related to Channel Open Probability %D 2011 %R 10.1124/mol.111.074476 %J Molecular Pharmacology %P mol.111.074476 %X The GABA type A receptor (GABAAR) is expressed ubiquitously throughout the brain and is a target for many therapeutic agents, including general anesthetics and benzodiazepines, which enhance receptor function by increasing the open probability (PO) of the ion channel. It is commonplace for in vitro studies of receptor pharmacology to use negative membrane holding potentials to mimic the resting potential of neurons and symmetrical chloride to eliminate Goldman rectification; resulting in chloride flow in the opposite direction of in vivo conditions. This critical difference is usually overlooked because the GABAAR has been reported to behave as an ohmic pore, but our results show that the current-voltage relationship is non-linear with respect to PO. Specifically, we found that currents were outwardly rectifying at low PO and linear at high PO. We confirmed the correlation between PO and rectification with a partial agonist, piperidine-4-sulfonic acid, and a gating impaired mutation, α1(L277A); both exhibited enhanced outward rectification. Furthermore, this correlation was independent of Goldman rectification and persisted in altered chloride gradient conditions, suggesting that rectification is linked to the direction of chloride flux. Finally, our results showed that the degree of potentiation by general anesthetics (etomidate, propofol, and isoflurane) was greater at negative membrane potentials. Traditional in vitro experiments will therefore over-estimate the action of positive allosteric modulators of the GABAAR. Our results show that the direction of driving force on the permeant ion, as well as, PO must be considered together in order to completely understand drug action on ligand-gated ion channels. %U https://molpharm.aspetjournals.org/content/molpharm/early/2011/10/31/mol.111.074476.full.pdf