TY - JOUR T1 - GABAA receptor activation in the allosteric coagonist model framework: relationship between EC50 and basal activity JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.110569 SP - mol.117.110569 AU - Gustav Akk AU - Daniel J Shin AU - Allison L Germann AU - Joseph H. Steinbach Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/11/17/mol.117.110569.abstract N2 - The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. Here, we use the model to examine the relationship between the EC50 for activation of the GABAA receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. The basal activity reflects receptor function in the absence of transmitter, and can be changed either by mutation to increase constitutive activity, or by addition of a second agonist (acting at a different site) to increase background activity. The model predicts that either mechanism for producing a change in basal activity will result in identical effects on the EC50. We examined receptor activation by GABA while changing the level of basal activity with the allosterically-acting anesthetics propofol, pentobarbital or alfaxalone, and found that the relationship between EC50 and basal activity was well-described by the concerted transition model. Changes in the basal activity by gain-of-function mutations also resulted in predictable changes in the EC50. Finally, we altered the number of GABA-binding sites by a mutation, and again found that the relationship could be well-described by the model. Overall, the results support the idea that interactions between the transmitter GABA and the allosteric agonists propofol, pentobarbital or alfaxalone can be understood as reflecting additive and independent free energy changes, without assuming any specific interactions. ER -