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• W4387026697 abstract "The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor. The energetic contributions are fixed and, once known, enable calculation of predicted receptor behavior at any concentration combination of agonist and potentiator. Here, we have examined the applicability of the coagonist model by measuring the relationship between the magnitude of receptor potentiation and the level of background activity. Ternary αβγ GABAA receptors were activated by GABA or the allosteric agonist propofol, or by a gain-of-function mutation, and etiocholanolone- or propofol-mediated potentiation of peak responses was measured. We show that the free energy change contributed by the modulators etiocholanolone or propofol is reduced at higher levels of control activity, thereby being in disagreement with basic principles of the coagonist model. Possible mechanisms underlying this discrepancy are discussed." @default.
• W4387026697 created "2023-09-26" @default.
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• W4387026697 date "2023-09-01" @default.
• W4387026697 modified "2023-10-18" @default.
• W4387026697 title "Potentiation of the GABAAR reveals variable energetic contributions by etiocholanolone and propofol" @default.
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• W4387026697 doi "https://doi.org/10.1016/j.bpj.2023.09.014" @default.
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