The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control agonist coapplied with the low-efficacy test agonist that binds to the same site(s). If the response to the combination is larger than the response to the control agonist alone, then the PA,max of the test agonist is greater than the PA of the control response. Conversely, if the response to the control agonist is reduced upon exposure to the test agonist, then the PA,max of the test agonist is smaller than the PA of the control response. The exact PA,max of the test agonist can be determined by testing its effect at different concentrations of the control agonist to estimate the PA at which the effect changes direction. The main advantage of this approach lies in the ability to use low, subsaturating concentrations of the test agonist. The model-based predictions are supported by observations from activation of heteromeric and homomeric GABAA receptors by combinations of high- and low-efficacy orthosteric agonists.
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6 January 2025
Methods and Approaches|
November 25 2024
Null method to estimate the maximal PA at subsaturating concentrations of agonist
Allison L. Germann
,
Allison L. Germann
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - review & editing)
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
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Spencer R. Pierce
,
Spencer R. Pierce
(Data curation, Formal analysis, Investigation)
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
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Joe Henry Steinbach
,
Joe Henry Steinbach
(Conceptualization, Formal analysis, Methodology, Writing - original draft, Writing - review & editing)
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
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Gustav Akk
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft)
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
Correspondence to Gustav Akk: [email protected]
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Allison L. Germann
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - review & editing
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
Spencer R. Pierce
Data curation, Formal analysis, Investigation
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
Joe Henry Steinbach
Conceptualization, Formal analysis, Methodology, Writing - original draft, Writing - review & editing
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
Gustav Akk
Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft
1Department of Anesthesiology,
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine
, St. Louis, MO, USA
Correspondence to Gustav Akk: [email protected]
Disclosures: G. Akk reported that the work was supported by a grant from National Institutes of Health National Institute of General Medical Sciences (R35GM140947) and funds from the Taylor Family Institute for Innovative Psychiatric Research at Washington University in St Louis. No other disclosures were reported.
Received:
July 16 2024
Revision Received:
October 10 2024
Accepted:
November 07 2024
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
National Institutes of Health
Funder(s):
National Institute of General Medical Sciences
- Award Id(s): R35GM140947
Funder(s):
Taylor Family Institute for Innovative Psychiatric Research
© 2024 Germann et al.
2024
Germann et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
This work is licensed under a
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
.
J Gen Physiol (2025) 157 (1): e202413644.
Article history
Received:
July 16 2024
Revision Received:
October 10 2024
Accepted:
November 07 2024
Citation
Allison L. Germann, Spencer R. Pierce, Joe Henry Steinbach, Gustav Akk; Null method to estimate the maximal PA at subsaturating concentrations of agonist. J Gen Physiol 6 January 2025; 157 (1): e202413644. doi: https://doi.org/10.1085/jgp.202413644
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